Publications by authors named "Stephen I Alexander"

149 Publications

Promotion of β-Catenin/Forkhead Box Protein O Signaling Mediates Epithelial Repair in Kidney Injury.

Am J Pathol 2021 Mar 19. Epub 2021 Mar 19.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia. Electronic address:

Fibrosis is characterized by progressive excessive deposition of matrix components and may lead to organ failure. Transforming growth factor-β (TGF-β) is a key cytokine involved in tissue repair and fibrosis. TGF-β's profibrotic signaling pathways converge at activation of β-catenin. β-Catenin is an important transcription cofactor whose function depends on its binding partner. Our previous studies demonstrated that promoting β-catenin binding to forkhead box protein O (Foxo) via inhibition of its binding to T-cell factor (TCF) reduced kidney fibrosis in experimental murine models. Herein, we investigated whether β-catenin/Foxo diverts TGF-β signaling from profibrotic to physiological epithelial healing. In an in vitro model of wound healing (scratch assay), and in an in vivo model of kidney injury, unilateral renal ischemia reperfusion, TGF-β treatment in combination with either ICG-001 or iCRT3 (β-catenin/TCF inhibitors) increased β-catenin/Foxo interaction, increased scratch closure by increased cell proliferation and migration, reduced the TGF-β-induced mesenchymal differentiation, and healed the ischemia reperfusion injury with less fibrosis. In addition, administration of ICG-001 or iCRT3 reduced the contractile activity induced by TGF-β in C1.1 cells. Together, our results indicate that redirection of β-catenin binding from TCF to Foxo promotes β-catenin/Foxo-mediated epithelial repair. Targeting β-catenin/Foxo may rebuild normal structure of injured kidney.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2021.03.005DOI Listing
March 2021

Australia and New Zealand renal gene panel testing in routine clinical practice of 542 families.

NPJ Genom Med 2021 Mar 4;6(1):20. Epub 2021 Mar 4.

KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC, Australia.

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-021-00184-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933190PMC
March 2021

Survival and transplant outcomes among young children requiring kidney replacement therapy.

Pediatr Nephrol 2021 Mar 1. Epub 2021 Mar 1.

School of Medicine, University of Western Australia, Perth, WA, Australia.

Background: Young children starting kidney replacement therapy (KRT) suffer high disease burden with unique impacts on growth and development, timing of transplantation and long-term survival. Contemporary long-term outcome data and how these relate to patient characteristics are necessary for shared decision-making with families, to identify modifiable risk factors and inform future research.

Methods: We examined outcomes of all children ≤ 5 years enrolled in the Australia and New Zealand Dialysis and Transplant Registry, commencing KRT 1980-2017. Primary outcomes were patient and graft survival. Final height attained was also examined. We used generalized additive modelling to investigate the relationship between age and graft loss over time post-transplant.

Results: In total, 388 children were included, of whom 322 (83%) received a kidney transplant. Cumulative 1-, 5- and 10-year patient survival probabilities were 93%, 86% and 83%, respectively. Death censored graft survival at 1, 5 and 10 years was 93%, 87% and 77%, respectively. Most children were at least 10 kg at transplantation (n = 302; 96%). A non-linear relationship between age at transplantation and graft loss was observed, dependent on time post-transplant, with increased risk of graft loss among youngest recipients both initially following transplantation and subsequently during adolescence. Graft and patient survival have improved in recent era.

Conclusions: Young children commencing KRT have good long-term survival and graft outcomes. Early graft loss is no reason to postpone transplantation beyond 10 kg, and among even the youngest recipients, late graft loss risk in adolescence remains one of the greatest barriers to improving long-term outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-021-04945-9DOI Listing
March 2021

One for All and All for One: The Triumph of the One Study.

Transplantation 2021 02;105(2):273-274

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, NSW, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003474DOI Listing
February 2021

Pro-inflammatory dopamine-2 receptor-specific T cells in paediatric movement and psychiatric disorders.

Clin Transl Immunology 2020 17;9(12):e1229. Epub 2020 Dec 17.

Brain Autoimmunity Group Kids Neuroscience Centre Kids Research at the Children's Hospital at Westmead Sydney NSW Australia.

Objectives: A dysregulated inflammatory response against the dopamine-2 receptor (D2R) has been implicated in movement and psychiatric disorders. D2R antibodies were previously reported in a subset of these patients; however, the role of T cells in these disorders remains unknown. Our objective was to identify and characterise pro-inflammatory D2R-specific T cells in movement and psychiatric disorders.

Methods: Blood from paediatric patients with movement and psychiatric disorders of suspected autoimmune and neurodevelopmental aetiology ( = 24) and controls ( = 16) was cultured with a human D2R peptide library, and D2R-specific T cells were identified by flow cytometric quantification of CD4CD25CD134 T cells. Cytokine secretion was analysed using a cytometric bead array and ELISA. HLA genotypes were examined in D2R-specific T-cell-positive patients. D2R antibody seropositivity was determined using a flow cytometry live cell-based assay.

Results: Three immunodominant regions of D2R, amino acid (aa)121-131, aa171-181 and aa396-416, specifically activated CD4 T cells in 8/24 patients. Peptides corresponding to these regions were predicted to bind with high affinity to the HLA of the eight positive patients and had also elicited the secretion of pro-inflammatory cytokines IL-2, IFN- γ, TNF, IL-6, IL-17A and IL-17F. All eight patients were seronegative for D2R antibodies.

Conclusion: Autoreactive D2R-specific T cells and a pro-inflammatory Th1 and Th17 cytokine profile characterise a subset of paediatric patients with movement and psychiatric disorders, further underpinning the theory of immune dysregulation in these disorders. These findings offer new perspectives into the neuroinflammatory mechanisms of movement and psychiatric disorders and can influence patient diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cti2.1229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780098PMC
December 2020

Correction to: Matrix metalloproteinase 9 induces endothelial-mesenchymal transition via Notch activation in human kidney glomerular endothelial cells.

BMC Mol Cell Biol 2020 Oct 21;21(1):72. Epub 2020 Oct 21.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, the University of Sydney, 176 Hawkesbury Road, Sydney, NSW, 2145, Australia.

An amendment to this paper has been published and can be accessed via the original article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12860-020-00318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576858PMC
October 2020

Renal tubular cell binding of β-catenin to TCF1 versus FoxO1 is associated with chronic interstitial fibrosis in transplanted kidneys.

Am J Transplant 2021 02 1;21(2):727-739. Epub 2020 Oct 1.

Centre for Transplant and Renal Research, University of Sydney at Westmead Institute for Medical Research, Westmead, Australia.

β-Catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of β-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. β-Catenin/FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation. and inflammatory fibrosis (P < .001). The relative binding of β-catenin/TCF1 versus β-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at 1 year (n = 131, all P < .001). The TF ratio was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717), and moderate fibrosis (AUC 0.769) using receiver operating characteristic analysis. An independent validation cohort (n = 76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% vs. 2.6%, P = .047), however, not with other outcomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of β-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.16287DOI Listing
February 2021

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

Am J Kidney Dis 2020 10 10;76(4):533-545. Epub 2020 Jul 10.

Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore.

Rationale & Objective: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD.

Study Design: An online 2-round Delphi survey in English, French, and Hindi languages.

Settings & Participants: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale.

Analytical Approach: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically.

Results: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals.

Limitations: Most participants completed the survey in English.

Conclusions: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.03.014DOI Listing
October 2020

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-KIDS) consensus workshops.

Kidney Int 2020 09 4;98(3):553-565. Epub 2020 Jul 4.

Department of Nephrology and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.05.054DOI Listing
September 2020

Gut Microbial Metabolites Induce Donor-Specific Tolerance of Kidney Allografts through Induction of T Regulatory Cells by Short-Chain Fatty Acids.

J Am Soc Nephrol 2020 07 1;31(7):1445-1461. Epub 2020 Jun 1.

Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.

Background: Short-chain fatty acids derived from gut microbial fermentation of dietary fiber have been shown to suppress autoimmunity through mechanisms that include enhanced regulation by T regulatory cells (Tregs).

Methods: Using a murine kidney transplantation model, we examined the effects on alloimmunity of a high-fiber diet or supplementation with the short-chain fatty acid acetate. Kidney transplants were performed from BALB/c(H2) to B6(H2) mice as allografts in wild-type and recipient mice lacking the G protein-coupled receptor GPR43 (the metabolite-sensing receptor of acetate). Allograft mice received normal chow, a high-fiber diet, or normal chow supplemented with sodium acetate. We assessed rejection at days 14 (acute) and 100 (chronic), and used 16S rRNA sequencing to determine gut microbiota composition pretransplantation and post-transplantation.

Results: Wild-type mice fed normal chow exhibited dysbiosis after receiving a kidney allograft but not an isograft, despite the avoidance of antibiotics and immunosuppression for the latter. A high-fiber diet prevented dysbiosis in allograft recipients, who demonstrated prolonged survival and reduced evidence of rejection compared with mice fed normal chow. Allograft mice receiving supplemental sodium acetate exhibited similar protection from rejection, and subsequently demonstrated donor-specific tolerance. Depletion of CD25 Tregs or absence of the short-chain fatty acid receptor GPR43 abolished this survival advantage.

Conclusions: Manipulation of the microbiome by a high-fiber diet or supplementation with sodium acetate modified alloimmunity in a kidney transplant model, generating tolerance dependent on Tregs and GPR43. Diet-based therapy to induce changes in the gut microbiome can alter systemic alloimmunity in mice, in part through the production of short-chain fatty acids leading to Treg cell development, and merits study as a potential clinical strategy to facilitate transplant acceptance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019080852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350991PMC
July 2020

A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder.

Development 2020 06 22;147(21). Epub 2020 Jun 22.

Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia

Laminin alpha 5 (LAMA5) is a member of a large family of proteins that trimerise and then polymerise to form a central component of all basement membranes. Consequently, the protein plays an instrumental role in shaping the normal development of the kidney, skin, neural tube, lung and limb, and many other organs and tissues. Pathogenic mutations in some laminins have been shown to cause a range of largely syndromic conditions affecting the competency of the basement membranes to which they contribute. We report the identification of a mutation in the polymerisation domain of LAMA5 in a patient with a complex syndromic disease characterised by defects in kidney, craniofacial and limb development, and by a range of other congenital defects. Using CRISPR-generated mouse models and biochemical assays, we demonstrate the pathogenicity of this variant, showing that the change results in a failure of the polymerisation of α/β/γ laminin trimers. Comparing these phenotypes with those apparent upon gene deletion in mice provides insights into the specific functional importance of laminin polymerisation during development and tissue homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.189183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540250PMC
June 2020

Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of CD4CD25FOXP3 Regulatory T Cells and Prolonged Human Islet Allograft Survival in Humanized Mice.

Diabetes 2020 08 7;69(8):1735-1748. Epub 2020 May 7.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, New South Wales, Australia

Islet transplantation is an emerging therapy for type 1 diabetes and hypoglycemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study, we established a diabetic humanized NOD-scidIL2Rγ (NSG) mouse model of T-cell-mediated human islet allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin-2 (IL-2) combined with low-dose rapamycin to prolong graft survival. NSG mice that had received renal subcapsular human islet allografts and were transfused with 1 × 10 of human spleen mononuclear cells reconstituted human CD45 cells that were predominantly CD3 T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3 × 10 IU/m or 1 × 10 IU/m) or rapamycin alone (0.5-1 mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet allograft survival. Graft survival was associated with expansion of CD4CD25FOXP3 regulatory T cells (Tregs) and enhanced transforming growth factor-β production by CD4 T cells. CD8 T cells showed reduced interferon-γ production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet allograft rejection by expanding CD4FOXP3 Tregs in vivo and suppressing effector cell function and could be the basis of effective tolerance-based regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db19-0525DOI Listing
August 2020

Identifying Outcomes Important to Patients with Glomerular Disease and Their Caregivers.

Clin J Am Soc Nephrol 2020 05 30;15(5):673-684. Epub 2020 Apr 30.

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.

Background And Objectives: Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices.

Design: We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically.

Results: Across 16 focus groups, 134 participants (range, 19-85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family.

Conclusions: Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.13101019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269216PMC
May 2020

The association between human leukocyte antigen eplet mismatches, de novo donor-specific antibodies, and the risk of acute rejection in pediatric kidney transplant recipients.

Pediatr Nephrol 2020 06 17;35(6):1061-1068. Epub 2020 Feb 17.

Centre for Kidney Research, Children's Hospital at Westmead, Sydney, Australia.

Background: The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown.

Methods: Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection.

Results: The cohort comprised 59 children (aged 0-18 years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07-1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01-1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99-34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25-115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54-186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64-57.72, p = 0.01).

Conclusions: Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04474-xDOI Listing
June 2020

Indirectly Activated Treg Allow Dominant Tolerance to Murine Skin-grafts Across an MHC Class I Mismatch After a Single Donor-specific Transfusion.

Transplantation 2020 07;104(7):1385-1395

Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead (CHW), NSW, Australia.

Background: Tolerance induced in stringent animal transplant models using donor-specific transfusions (DST) has previously required additional immunological manipulation. Here, we demonstrate a dominant skin-allograft tolerance model induced by a single DST across an major histocompatibility class I mismatch in an unmanipulated B6 host.

Methods: C57BL/6 (H-2) (B6) mice were injected intravenously with splenocytes from B6.C.H-2 (H-2k) (bm1) or F1 (B6 × bm1) mice before skin transplantation. Mice were transplanted 7 days postinjection with donor (bm1 or F1) and third-party B10.BR (H-2) skin grafts.

Results: B6 hosts acutely rejected skin grafts from B6.C.H-2 (bm1) and F1 (B6 × bm1) mice. A single transfusion of F1 splenocytes into B6 mice without any additional immune modulation led to permanent acceptance of F1 skin grafts. This graft acceptance was associated with persistence of donor cells long-term in vivo. The more rapid removal of DST bm1 cells than F1 cells was reduced by natural killer-cell depletion. Tolerant grafts survived an in vivo challenge with naive splenocytes. Both CD4CD25 and CD4CD25 T cells from F1 DST treated B6 mice suppressed alloproliferation in vitro. Tolerance was associated with expansion of peripheral Foxp3CD4CD25 regulatory T cells (Treg) and increased forkhead box P3 (Foxp3) expression in tolerant grafts. In tolerant mice, Foxp3 Treg arises from the proliferation of indirectly activated natural Foxp3 Treg (nTreg) and depletion of Foxp3 Treg abrogates skin-graft tolerance.

Conclusions: This study demonstrates that the persistence of transfused semiallogeneic donor cells mismatched at major histocompatibility class I can enhance tolerance to subsequent skin allografts through indirectly expanded nTreg leading to dominant tolerance without additional immunological manipulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003173DOI Listing
July 2020

Regulatory innate lymphoid cells suppress innate immunity and reduce renal ischemia/reperfusion injury.

Kidney Int 2020 01 23;97(1):130-142. Epub 2019 Aug 23.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Innate lymphoid cells are a recently recognized group of immune cells with critical roles in tissue homeostasis and inflammation. Regulatory innate lymphoid cells are a newly identified subset of innate lymphoid cells, which play a suppressive role in the innate immune response, favoring the resolution of intestinal inflammation. However, the expression and role of regulatory innate lymphoid cells in kidney has not been reported. Here, we show that regulatory innate lymphoid cells are present in both human and mouse kidney, express similar surface markers and form a similar proportion of total kidney innate lymphoid cells. Regulatory innate lymphoid cells from kidney were expanded in vitro with a combination of IL-2, IL-7 and transforming growth factor-β. These cells exhibited immunosuppressive effects on innate immune cells via secretion of IL-10 and transforming growth factor-β. Moreover, treatment with IL-2/IL-2 antibody complexes (IL-2C) promoted expansion of regulatory innate lymphoid cells in vivo, and prevent renal ischemia/reperfusion injury in Rag-/- mice that lack adaptive immune cells including Tregs. Depletion of regulatory innate lymphoid cells with anti-CD25 antibody abolished the beneficial effects of IL-2C in the Rag-/- mice. Adoptive transfer of ex vivo expanded regulatory innate lymphoid cells improved renal function and attenuated histologic damage when given before or after induction of ischemia/reperfusion injury in association with reduction of neutrophil infiltration and induction of reparative M2 macrophages in kidney. Thus, our study shows that regulatory innate lymphoid cells suppress innate renal inflammation and ischemia/reperfusion injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2019.07.019DOI Listing
January 2020

Allograft outcome following repeat transplantation of patients with non-adherence-related first kidney allograft failure: a population cohort study.

Transpl Int 2019 Dec 1;32(12):1247-1258. Epub 2019 Oct 1.

Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia.

Nonadherence is an important risk factor for premature allograft failure after kidney transplantation, but outcomes after re-transplantation remain uncertain. Using data from the Australian and New Zealand Dialysis and Transplant registry, the associations between causes of first allograft failure and acute rejection-related and non-adherence-related allograft failure following re-transplantation were examined using competing risk analyses, treating the respective alternative causes of allograft failure and death with functioning graft as competing events. Fifty-nine of 2450 patients (2%) lost their first allografts from nonadherence. Patients who lost their first kidney allograft from nonadherence were younger at the time of first kidney allograft failure but waited longer for a second allograft (>5 years: 54% vs. 20%, P < 0.001) compared with other causes. Compared with patients who lost their first allograft from causes other than nonadherence, the adjusted subdistribution hazard ratio (HR and 95% CI) for acute rejection-related second allograft failure was 0.58 (0.08, 4.07; P = 0.582) for patients with allograft failure attributed to nonadherence and was 6.30 (1.34, 29.67; P = 0.020) for non-adherence-related second allograft failure. In this cohort of transplant recipients who have received second allografts, first allograft failure secondary to nonadherence was associated with a marginally greater risk of allograft failure attributed to nonadherence in subsequent transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tri.13492DOI Listing
December 2019

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection.

J Am Soc Nephrol 2019 08 5;30(8):1481-1494. Epub 2019 Jul 5.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;

Background: In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies.

Methods: We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort.

Results: Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss.

Conclusions: Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2018111098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683710PMC
August 2019

Promotion of β-catenin/Foxo1 signaling ameliorates renal interstitial fibrosis.

Lab Invest 2019 11 26;99(11):1689-1701. Epub 2019 Jun 26.

Centre for Transplantation and Renal Research, The University of Sydney at The Westmead Institute for Medical Research, Sydney, Australia.

Transforming growth factor β (TGF-β) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-β to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. β-catenin is a common co-factor in most TGF-β signaling pathways. β-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Forkhead box O (Foxo) to promote cell survival under oxidative stress. Using a proximity ligation assay in human kidney biopsies, we found that β-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas β-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that β-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-β1-induced profibrotic protein expression using a CRISPR/cas9 knockout of Foxo1 or TCF1 in murine kidney tubular epithelial C1.1 cells. Co-administration of TGF-β with a small molecule inhibitor of β-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest β-catenin/Foxo as a therapeutic target in kidney fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41374-019-0276-zDOI Listing
November 2019

Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection.

JCI Insight 2019 06 6;4(11). Epub 2019 Jun 6.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Commonly available clinical parameters fail to predict early acute cellular rejection (EAR, occurring within 6 months after transplant), a major risk factor for graft loss after kidney transplantation. We performed whole-blood RNA sequencing at the time of transplant in 235 kidney transplant recipients enrolled in a prospective cohort study (Genomics of Chronic Allograft Rejection [GoCAR]) and evaluated the relationship of pretransplant transcriptomic profiles with EAR. EAR was associated with downregulation of NK and CD8+ T cell gene signatures in pretransplant blood. We identified a 23-gene set that predicted EAR in the discovery (n = 81, and AUC = 0.80) and validation (n = 74, and AUC = 0.74) sets. Exclusion of recipients with 5 or 6 HLA donor mismatches increased the AUC to 0.89. The risk score derived from the gene set was also significantly associated with acute cellular rejection after 6 months, antibody-mediated rejection and/or de novo donor-specific antibodies, and graft loss in a cohort of 154 patients, combining the validation set and additional GoCAR patients with surveillance biopsies between 6 and 24 months (n = 80) posttransplant. This 23-gene set is a potentially important new tool for determination of the recipient's immunological risk before kidney transplantation, and facilitation of an individualized approach to immunosuppressive therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.127543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629121PMC
June 2019

Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus.

Nat Commun 2019 05 17;10(1):2201. Epub 2019 May 17.

Department of Immunology, The Canberra Hospital, Garran, 2601, ACT, Australia.

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10242-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525203PMC
May 2019

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

Genet Med 2019 09 10;21(9):2103-2115. Epub 2019 Apr 10.

Drs. Farley, Polo and Ho, Colonial Heights, VA, USA.

Purpose: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache.

Methods: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members.

Results: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis.

Conclusion: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0476-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752478PMC
September 2019

Identifying Important Outcomes for Young People With CKD and Their Caregivers: A Nominal Group Technique Study.

Am J Kidney Dis 2019 07 15;74(1):82-94. Epub 2019 Mar 15.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Rationale & Objective: Chronic kidney disease (CKD) has wide-ranging and long-term consequences for young people and their families. The omission of outcomes that are important to young people with CKD and their caregivers limits knowledge to guide shared decision making. We aimed to identify the outcomes that are important to young people with CKD and their caregivers.

Study Design: We used the nominal group technique whereby participants identified and ranked outcomes and explained their priorities.

Settings & Participants: Young people with CKD (stages 1-5, dialysis, or transplantation) and their caregivers were purposively sampled from 6 centers across Australia, the United States, and Canada.

Analytical Approach: Importance scores were calculated (scale of 0-1), and qualitative data were analyzed thematically.

Results: 34 patients (aged 8-21 years) and 62 caregivers participated in 16 groups and identified 48 outcomes. The 5 highest ranked outcomes for patients were survival (importance score, 0.25), physical activity (0.24), fatigue (0.20), lifestyle restrictions (0.20), and growth (0.20); and for caregivers, kidney function (0.53), survival (0.28), infection (0.22), anemia (0.20), and growth (0.17). 12 themes were identified reflecting their immediate and current priorities (wanting to feel normal, strengthening resilience, minimizing intrusion into daily life, imminent threats to life, devastating family burdens, and seeking control over health) and considerations regarding future impacts (protecting health/development, remaining hopeful, concern for limited opportunities, prognostic uncertainty, dreading painful and invasive procedures, and managing expectations).

Limitations: Only English-speaking participants were recruited.

Conclusions: Kidney function, infection, survival, and growth were the highest priorities for patients with CKD and their caregivers. Young people with CKD also prioritized highly the outcomes that directly affected their lifestyle and sense of normality, while caregiver's highest priorities concerned the long-term health of their child, current health problems, and the financial and family burdens of caring for a child with CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2018.12.040DOI Listing
July 2019

Dendritic cell-targeted CD40 DNA vaccine suppresses Th17 and ameliorates progression of experimental autoimmune glomerulonephritis.

J Leukoc Biol 2019 04 27;105(4):809-819. Epub 2019 Feb 27.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.

The CD40-CD40L costimulatory pathway is critical for T cell activation in autoimmune disease. We have previously found that blocking the CD40-CD40L pathway using a dendritic cell-targeted CD40 DNA (DEC-CD40) vaccine prevented the development of Heymann nephritis. In this study, we explored the effect of a DEC-CD40 vaccine in the treatment of experimental autoimmune glomerulonephritis (EAG), an animal model of human Goodpasture's disease induced by antigen α3IV-NC1. DEC-CD40 vaccine given at week 3 and week 6 after 3IV-NC1 injection reduced kidney structural and functional injury significantly in EAG. DEC-CD40 vaccination suppressed Th17 cell numbers and Th17 immune responses in kidney and spleen, but did not alter Th1 cells number and responses. Serum derived from rats with DEC-CD40 vaccination suppressed Th17 differentiation, but not Th1 differentiation in vitro. Furthermore, B cell activation, driven by Th17 cytokines, was suppressed by serum from rats vaccinated with DEC-CD40. A DNA vaccine encoding CD40 and targeting dendritic cell, ameliorates kidney injury in both early and late stages in EAG rats, indicating DEC-CD40 vaccination has a therapeutic role in EAG. Its effect is associated with the reduction of Th17 differentiation and Th17-mediated B cell activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.5A0818-333RDOI Listing
April 2019

Increased splenic human CD4:CD8 T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice.

Transpl Immunol 2019 06 8;54:38-46. Epub 2019 Feb 8.

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2252, Australia; Molecular Horizons, University of Wollongong, Wollongong, NSW 2252, Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2252, Australia. Electronic address:

Graft-versus-host disease (GVHD) is a frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT) with current therapies limited to general immunosuppression. Humanized mouse models of GVHD are emerging as valuable intermediaries to allow translation of findings from allogeneic mouse models to humans to prevent and treat this disease, but such models require further characterization. In this study, humanized mice were generated by injecting immunodeficient non-obese diabetic severe combined immunodeficiency interleukin (IL)-2 receptor γ common chain null (NSG) mice with human peripheral blood mononuclear cells (hPBMCs). Clinical GVHD development was assessed using established scoring criteria (weight loss, posture, activity, fur texture and skin integrity). Differences between humanized NSG mice that developed clinical or subclinical GVHD were then compared. Both groups of mice demonstrated similar frequencies of human leukocyte engraftment. In contrast, mice that developed clinical GVHD demonstrated increased histological damage compared to mice with subclinical GVHD. Furthermore, mice with clinical GVHD exhibited increases in the splenic human CD4:CD8 T cell ratio, serum human interferon (IFN)-γ and intestinal human IL-17 expression compared to mice with subclinical GVHD. These cellular and molecular changes could be used as potential markers of disease progression in this preclinical model. This study also provides further insights into GVHD development which may be relevant to human HSCT recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trim.2019.02.003DOI Listing
June 2019

Infectious Disease Transmission in Solid Organ Transplantation: Donor Evaluation, Recipient Risk, and Outcomes of Transmission.

Transplant Direct 2019 Jan 20;5(1):e416. Epub 2018 Dec 20.

Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL.

In 2016, the Transplantation Society of Australia and New Zealand, with the support of the Australian Government Organ and Tissue authority, commissioned a literature review on the topic of infectious disease transmission from deceased donors to recipients of solid organ transplants. The purpose of this review was to synthesize evidence on transmission risks, diagnostic test characteristics, and recipient management to inform best-practice clinical guidelines. The final review, presented as a special supplement in Transplantation Direct, collates case reports of transmission events and other peer-reviewed literature, and summarizes current (as of June 2017) international guidelines on donor screening and recipient management. Of particular interest at the time of writing was how to maximize utilization of donors at increased risk for transmission of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, given the recent developments, including the availability of direct-acting antivirals for hepatitis C virus and improvements in donor screening technologies. The review also covers emerging risks associated with recent epidemics (eg, Zika virus) and the risk of transmission of nonendemic pathogens related to donor travel history or country of origin. Lastly, the implications for recipient consent of expanded utilization of donors at increased risk of blood-borne viral disease transmission are considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TXD.0000000000000852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324914PMC
January 2019

Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation.

Nephrol Dial Transplant 2019 11;34(11):1853-1863

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.

Background: Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs.

Methods: To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN.

Results: Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103- DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice.

Conclusion: Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfy385DOI Listing
November 2019

Research priorities for childhood chronic conditions: a workshop report.

Arch Dis Child 2019 03 2;104(3):237-245. Epub 2018 Oct 2.

Centre for Kidney Research, The Children's Hospital, Westmead, New South Wales, Australia.

Background: Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy.

Objective: To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices.

Setting: An Australian paediatric hospital and health consumer organisations.

Methods: Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed.

Results: Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services).

Conclusion: Research priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/archdischild-2018-315628DOI Listing
March 2019

Murine Skin-resident γδT Cells Impair the Immune Response to HSV in Skin.

Infect Disord Drug Targets 2020 ;20(3):309-317

Kids Research Institute, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia

Background: HSV is an important cause of brain infection. Virus entry is often through breeches in the skin. γδT cells play an immunoprotective role in mice after corneal, genital or footpad (subcutaneous) HSV infection.

Methods: Here we report that the presence of γδT cells in murine skin is associated with increased severity of herpetic disease, reduced protective cytokine responses and increased viral spread from the skin to the sensory ganglia in the zosteriform model. γδT cell-deficient (TCR δ -/-) mice displayed significantly decreased herpetic lesion severity after flank HSV infection compared to WT C57BL/6 controls at both primary and secondary skin infection sites.

Results: Viral titer at the primary skin site was similar to WT mice in γδT cell-deficient mice, but was significantly decreased in the ganglia and secondary skin site. γδT cell-deficient mice showed increased Th1 responses by both T cells and non-T cells at the primary site, and decreased T-cell Th17 responses and immune infiltration at the secondary site.

Conclusion: Cytokine responses of epidermal and dermal γδT cells to HSV also differed in WT mice (Th1 in epidermis, and Th17 in the dermis), suggesting a functional dichotomy between these two subsets. Our data suggest that in contrast to other mouse models of HSV infection, skinresident γδT cells promote the pathogenesis of HSV in skin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1871526518666181001123816DOI Listing
April 2021