Publications by authors named "Lisbeth A Welniak"

32 Publications

The Fourth International Workshop on Clinical Transplant Tolerance.

Am J Transplant 2021 01 22;21(1):21-31. Epub 2020 Jul 22.

Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.
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http://dx.doi.org/10.1111/ajt.16139DOI Listing
January 2021

Providing researchers with online access to NHLBI biospecimen collections: The results of the first six years of the NHLBI BioLINCC program.

PLoS One 2017 14;12(6):e0178141. Epub 2017 Jun 14.

Information Management Services, Inc., Calverton, Maryland, United States of America.

The National Heart, Lung, and Blood Institute (NHLBI), within the United States' National Institutes of Health (NIH), established the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) in 2008 to develop the infrastructure needed to link the contents of the NHLBI Biorepository and the NHLBI Data Repository, and to promote the utilization of these scientific resources by the broader research community. Program utilization metrics were developed to measure the impact of BioLINCC on Biorepository access by researchers, including visibility, program efficiency, user characteristics, scientific impact, and research types. Input data elements were defined and are continually populated as requests move through the process of initiation through fulfillment and publication. This paper reviews the elements of the tracking metrics which were developed for BioLINCC and reports the results for the first six on-line years of the program.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178141PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470669PMC
September 2017

2015 proceedings of the National Heart, Lung, and Blood Institute's State of the Science in Transfusion Medicine symposium.

Transfusion 2015 Sep 10;55(9):2282-90. Epub 2015 Aug 10.

Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland.

On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three "classical" transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small-group breakout sessions, and large-group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross-cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.
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http://dx.doi.org/10.1111/trf.13250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573332PMC
September 2015

Strategies for more rapid translation of cellular therapies for children: a US perspective.

Pediatrics 2013 Aug 8;132(2):351-8. Epub 2013 Jul 8.

Blood Systems Research Institute, San Francisco, California, USA.

Clinical trials for pediatric diseases face many challenges, including trial design, accrual, ethical considerations for children as research subjects, and the cost of long-term follow-up studies. In September 2011, the Production Assistance for Cellular Therapies Program, funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, sponsored a workshop, "Cell Therapy for Pediatric Diseases: A Growing Frontier," with the overarching goal of optimizing the path of discovery in research involving novel cellular therapeutic interventions for debilitating pediatric conditions with few or no available treatment options. Academic and industry investigators in the fields of cellular therapy and regenerative medicine described the obstacles encountered in conducting a clinical trial from concept to conclusion. Patient and parent advocates, bioethicists, biostatisticians, regulatory representatives from the US Food and Drug Administration, and translational scientists actively participated in this workshop, seeking to identify the unmet needs specific to cellular therapies and treatment of pediatric diseases and propose strategies to facilitate the development of novel therapies. In this article we summarize the obstacles and potential corrective strategies identified by workshop participants to maximize the speed of cell therapy translational research for childhood diseases.
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http://dx.doi.org/10.1542/peds.2012-3383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727672PMC
August 2013

Research opportunities in optimizing storage of red blood cell products.

Transfusion 2014 Feb 15;54(2):483-94. Epub 2013 May 15.

American Red Cross, Rockville, Maryland; NIH NHLBI, Bethesda, Maryland.

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http://dx.doi.org/10.1111/trf.12244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760974PMC
February 2014

IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation.

J Immunol 2012 Aug 9;189(4):2033-42. Epub 2012 Jul 9.

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR(-/-)) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to elucidate further the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR(-/-) or IFN-γ knockout (IFN-γ(-/-)) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR(-/-) T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFN-γ(-/-) T cells. Increases in lung GVHD did occur in mice with donor IFN-γR(-/-) T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR(-/-) T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR(-/-) T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-γ on host tissues and cell effector functions in GVHD/GVT.
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http://dx.doi.org/10.4049/jimmunol.1102853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509544PMC
August 2012

The triterpenoid CDDO-Me promotes hematopoietic progenitor expansion and myelopoiesis in mice.

Biol Blood Marrow Transplant 2012 Mar 17;18(3):396-405. Epub 2011 Nov 17.

Department of Dermatology, University of California, Davis, Sacramento, California 95817, USA.

The synthetic triterpenoid CDDO-Me has been shown to directly inhibit the growth of myeloid leukemias and lends itself to a wide array of therapeutic indications, including inflammatory conditions, because of its inhibition of NF-κB. We have previously demonstrated protection from acute graft-versus-host disease after CDDO-Me administration in an allogeneic bone marrow transplantation model. In the current study, we observed that CDDO-Me promoted myelopoiesis in both naive and transplanted mice. This effect was dose dependent, as high doses of CDDO-Me inhibited myeloid growth in vitro. All lineages (granulocyte macrophage colony-forming unit, BFU-E) were promoted by CDDO-Me. We then compared the effects with granulocyte colony-stimulating factor, a known inducer of myeloid expansion and mobilization from the bone marrow. Whereas both drugs induced terminal myeloid expansion in the spleen, peripheral blood, and bone marrow, granulocyte colony-stimulating factor only induced granulocyte macrophage colony-forming unit precursors in the spleen, while CDDO-Me increased these precursors in the spleen and bone marrow. After sublethal total-body irradiation, mice pretreated with CDDO-Me further displayed an accelerated recovery of myeloid progenitors and total nucleated cells in the spleen. A similar expansion of myeloid and myeloid progenitors was noted with CDDO-Me treatment after syngeneic bone marrow transplantation. Combined, these data suggest that CDDO-Me may be of use posttransplantation to accelerate myeloid recovery in addition to the prevention of graft-versus-host disease.
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http://dx.doi.org/10.1016/j.bbmt.2011.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502000PMC
March 2012

The triterpenoid CDDO-Me delays murine acute graft-versus-host disease with the preservation of graft-versus-tumor effects after allogeneic bone marrow transplantation.

Biol Blood Marrow Transplant 2010 Jun 23;16(6):739-50. Epub 2010 Mar 23.

Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, Nevada, USA.

The occurrence of acute graft-versus-host disease (aGVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) can inhibit murine early aGVHD, but antitumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from lethal aGVHD compared to CDDO. This correlated with reduced TNF-alpha production, reduced donor T cell proliferation, and decreased adhesion molecule (alpha(4)beta(7) integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying aGVHD, while preserving or possibly even augmenting GVT effects.
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http://dx.doi.org/10.1016/j.bbmt.2010.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866806PMC
June 2010

Activated allogeneic NK cells as suppressors of alloreactive responses.

Biol Blood Marrow Transplant 2010 Jun 1;16(6):772-81. Epub 2010 Mar 1.

Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou, People's Republic of China.

Donor NK cells have been shown to be able to promote engraftment during allogeneic bone marrow transplantation. They could specifically suppress or delete host reactive cells, thereby facilitating engraftment of donor marrow. To further elucidate the mechanism, we showed that activated H2(d) ALAK cells (adherent lymphokine activated killer, IL-2 activated T cell-depleted bone marrow and spleen cells) from BALB/c mice significantly suppressed the proliferation of H2(b) splenocytes from C57BL/6 mice in mixed lymphocyte responses (MLR) stimulated with irradiated H2(d) splenocytes from BALB/c mice (P < .01). The ability for H2(b) splenocytes to kill H2(d) tumor targets was also significantly inhibited by activated H2(d) ALAK cells (P < .01). The same number of H2(b) ALAK cells or H2(d) splenocytes did not show the same suppressive effect. These results suggested that activated H2(d) ALAK cells could specifically suppress the anti-H2(d) activity of the H2(b) splenocytes. Anti-tumor growth factor (TGF)beta antibody blockade did not diminish this suppressive effect of ALAK cells, suggesting that this activity is not dependent on TGF-beta secretion. ALAKs from gld (FasL mutant) mice suppressed the allo-responses as well as the wild-type ALAK cells. The ALAKs from pfp (perforin knockout) mice did not completely block the inhibitory effect, which suggested that the suppressive effect of the allogeneic ALAK cells could be partially caused by perforin-mediated killing. We further demonstrated that donor ALAK cells could promote engraftment by suppressing host alloreactive responses in a nonmyeloablative allogeneic BMT model. These studies suggest that activated donor NK cells specifically suppress the alloreactive cells and provide a promising way to promote donor engraftment without involving systemic and nonspecific suppression of the immune system.
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http://dx.doi.org/10.1016/j.bbmt.2010.02.023DOI Listing
June 2010

Proteasome inhibition and allogeneic hematopoietic stem cell transplantation: a review.

Biol Blood Marrow Transplant 2009 Dec;15(12):1502-12

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachustts, USA.

The proteasome and its associated ubiquitin protein modification system have proved to be an important therapeutic target in the treatment of multiple myeloma and other cancers. In addition to direct antitumor effects, proteasome inhibition also exerts strong effects on nonneoplastic immune cells. This indicates that proteasome inhibition, through the use of agents like bortezomib, could be used therapeutically to modulate immune responses. In this review we explore the emerging data, both preclinical and clinical, highlighting the importance of proteasome targeting of immunologic responses, primarily in the context of allogeneic hematopoietic stem cell transplantation (HSCT), both for the control of transplant-related toxicities like acute and chronic graft-versus-host disease (aGVHD, cGHVHD), and for improved malignant disease control after allogeneic HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2009.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501140PMC
December 2009

Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease.

Expert Opin Pharmacother 2008 Sep;9(13):2305-16

University of Nevada, University of Nevada School of Medicine, Department of Microbiology and Immunology, Mail Stop 199, Reno, NV 89557, USA.

Background: Allogeneic hematopoietic stem cell transplantation offers great promise for the treatment of a variety of diseases including malignancies and other diseases of hematopoietic origin. However, morbidity and mortality due to graft-versus-host disease (GVHD) remain a major barrier to its application.

Objective: This review will provide an overview of the pathophysiology of GVHD and discuss the recent advances in GVHD management in both preclinical and clinical studies.

Methods: An extensive literature search on PubMed from 1995 to 2008 was performed.

Results/conclusion: There has been much progress in our understanding of GVHD and finding new means to control acute GVHD. While these approaches hold promise, as yet none has been able to replace the standard methods we may use routinely to decrease the incidence of the condition.
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http://dx.doi.org/10.1517/14656566.9.13.2305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658813PMC
September 2008

CTL-promoting effects of CD40 stimulation outweigh B cell-stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus.

J Immunol 2008 Jul;181(1):47-61

Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA.

CD40/CD40L signaling promotes both B cell and CTL responses in vivo, the latter being beneficial in tumor models. Because CTL may also limit autoreactive B cell expansion in lupus, we asked whether an agonist CD40 mAb would exacerbate lupus due to B cell stimulation or would improve lupus due to CTL promotion. These studies used an induced model of lupus, the parent-into-F1 model in which transfer of DBA/2 splenocytes into B6D2F1 mice induces chronic lupus-like graft-vs-host disease (GVHD). Although agonist CD40 mAb treatment of DBA-->F1 mice initially exacerbated B cell expansion, it also strongly promoted donor CD8 T cell engraftment and cytolytic activity such that by 10 days host B cells were eliminated consistent with an accelerated acute GVHD. CD40 stimulation bypassed the requirement for CD4 T cell help for CD8 CTL possibly by licensing dendritic cells (DC) as shown by the following: 1) greater initial activation of donor CD8 T cells, but not CD4 T cells; 2) earlier activation of host DC; 3) host DC expansion that was CD8 dependent and CD4 independent; and 4) induction of acute GVHD using CD4-depleted purified DBA CD8+ T cells. A single dose of CD40 mAb improved lupus-like renal disease at 12 wk, but may not suffice for longer periods consistent with a need for continuing CD8 CTL surveillance. These results demonstrate that in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, CTL promotion is both feasible and beneficial and the CTL-promoting properties of CD40 stimulation outweigh the B cell-stimulatory properties.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613003PMC
http://dx.doi.org/10.4049/jimmunol.181.1.47DOI Listing
July 2008

Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation.

Blood 2008 Aug 6;112(4):1522-9. Epub 2008 Jun 6.

Department of Microbiology and Immunology, University of Nevada, School of Medicine, Reno, NV 89557, USA.

Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4(+) but not CD8(+) T cells from the donor graft. The improved survival correlated with markedly reduced serum TNFalpha but not IFNgamma levels. Transfer of Tnf(-/-) T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8(+) T cells resulted in enhanced GVT response, which was dependent on donor CD8(+) T cell-derived IFNgamma. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4(+) T cells from the graft or by inhibiting TNFalpha.
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http://dx.doi.org/10.1182/blood-2008-03-143461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515132PMC
August 2008

Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network.

Cell Immunol 2008 Mar-Apr;252(1-2):111-21. Epub 2008 Mar 4.

Department of Physiology and Cell Biology, UNR Cytometry Center and Reno, NV 89557, USA.

Neuroendocrine hormones such as growth hormone (GH) and prolactin (PRL) have been demonstrated to accelerate the recovery of the immune response after chemotherapy and bone marrow transplantation and to enhance the restoration of immunity in individuals infected with HIV and in normal individuals with compromised immune systems associated with aging. As the mechanism of action of these hormones has been elucidated, it has become clear that they are integral members of the immunological cytokine/chemokine network and share regulatory mechanisms with a wide variety of cytokines and chemokines. The members of this cytokine network induce and can be regulated by members of the suppressor of cytokine signaling (SOCS) family of intracellular proteins. In order to take advantage of the potential beneficial effects of hormones such as GH or PRL, it is essential to take into consideration the overall cytokine network and the regulatory effects of SOCS proteins.
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http://dx.doi.org/10.1016/j.cellimm.2007.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777337PMC
August 2008

Regulatory and conventional CD4+ T cells show differential effects correlating with PD-1 and B7-H1 expression after immunotherapy.

J Immunol 2008 Mar;180(5):2981-8

Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA.

Recently, our laboratory reported that secondary CD8+ T cell-mediated antitumor responses were impaired following successful initial antitumor responses using various immunotherapeutic approaches. Although immunotherapy stimulated significant increases in CD8+ T cell numbers, the number of CD4+ T cells remained unchanged. The current investigation revealed a marked differential expansion of CD4+ T cell subsets. Successful immunotherapy surprisingly resulted in an expansion of CD4+Foxp3+ regulatory T (Treg) cells concurrent with a reduction of conventional CD4+ T (Tconv) cells, despite the marked antitumor responses. Following immunotherapy, we observed differential up-regulation of PD-1 on the surface of CD4+Foxp3+ Treg cells and CD4+Foxp3- Tconv cells. Interestingly, it was the ligand for PD-1, B7-H1 (PDL-1), that correlated with Tconv cell loss after treatment. Furthermore, IFN-gamma knockout (IFN-gamma-/-) and IFN-gamma receptor knockout (IFN-gammaR-/-) animals lost up-regulation of surface B7-H1 even though PD-1 expression of Tconv cells was not changed, and this correlated with CD4+ Tconv cell increases. These results suggest that subset-specific expansion may contribute to marked shifts in the composition of the T cell compartment, potentially influencing the effectiveness of some immunotherapeutic approaches that rely on IFN-gamma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408862PMC
http://dx.doi.org/10.4049/jimmunol.180.5.2981DOI Listing
March 2008

The synthetic triterpenoid, CDDO, suppresses alloreactive T cell responses and reduces murine early acute graft-versus-host disease mortality.

Biol Blood Marrow Transplant 2007 May 26;13(5):521-9. Epub 2007 Feb 26.

Department of Microbiology and Immunology, University of Nevada, Reno, Nevada, USA.

Acute graft-versus-host disease (aGVHD) still remains one of the life-threatening complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation of alloreactive donor T cell responses, as well as cytokine secretion is a potential therapeutic approach for the prevention of aGVHD. The synthetic triterpenoid, CDDO (2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid), exhibits potent antitumor activity and has also been shown to mediate anti-inflammatory and immunomodulatory effects. We therefore wanted to assess the effects of CDDO on early lethal aGVHD. In this study, we found that CDDO significantly inhibited in vitro mixed lymphocyte responses and preferentially promoted the apoptosis of proliferating but not resting alloreactive T cells. Using a full major histocompatibility complex (MHC)-disparate murine aGVHD model, we found that the administration of CDDO immediately after transplantation significantly decreased liver pathology as determined by histologic assessment and prolonged survival in mice. Importantly, administration of CDDO did not adversely impair donor myeloid reconstitution as determined by peripheral blood cell count and the extent of donor chimerism. These findings indicate that CDDO has a significant immunomodulatory effects in vitro and on early lethal aGVHD development, particularly affecting the liver, in a murine allo-HSCT model.
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http://dx.doi.org/10.1016/j.bbmt.2006.12.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559277PMC
May 2007

IFN-gamma mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy.

Nat Med 2007 Mar 4;13(3):354-60. Epub 2007 Mar 4.

Department of Microbiology and Immunology, University of Nevada at Reno, Reno, Nevada 89557, USA.

Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (T(H)1) cytokines such as interferon-gamma (IFN-gamma). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-gamma. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-gamma responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.
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http://dx.doi.org/10.1038/nm1554DOI Listing
March 2007

Immunobiology of allogeneic hematopoietic stem cell transplantation.

Annu Rev Immunol 2007 ;25:139-70

Department of Microbiology and Immunology, University of Nevada, Reno, Nevada 89557, USA.

Allogeneic hematopoietic stem cell transplantation (HSCT) has evolved into an effective adoptive cellular immunotherapy for the treatment of a number of cancers. The immunobiology of allogeneic HSCT is unique in transplantation in that it involves potential immune recognition and attack between both donor and host. Much of the immunobiology of allogeneic HSCT has been gleaned from preclinical models and correlation with clinical observations. We review our current understanding of some of the issues that affect the success of this therapy, including host-versus-graft (HVG) reactions, graft-versus-host disease (GVHD), graft-versus-tumor (GVT) activity, and restoration of functional immunity to prevent transplant-related opportunistic infections. We also review new strategies to optimize the GVT and improve overall immune function while reducing GVHD and graft rejection.
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http://dx.doi.org/10.1146/annurev.immunol.25.022106.141606DOI Listing
June 2007

Stimulation through CD40 on mouse and human renal cell carcinomas triggers cytokine production, leukocyte recruitment, and antitumor responses that can be independent of host CD40 expression.

J Immunol 2006 Jun;176(11):6543-52

Laboratory of Experimental Immunology, National Cancer Institute for Cancer Research, Frederick, MD 21702-1201, USA.

CD40, a member of the TNFR superfamily, is expressed on a variety of host immune cells, as well as some tumors. In this study, we show that stimulation of CD40 expressed on both mouse and human renal carcinoma cells (RCCs) triggers biological effects in vitro and in vivo. Treatment of the CD40+ Renca mouse RCC tumor cells in vitro with an agonistic anti-CD40 Ab induced strong expression of the genes and proteins for GM-CSF and MCP-1, and induced potent chemotactic activity. Similarly, administration of alphaCD40 to both wild-type and CD40-/- mice bearing Renca tumors resulted in substantial amounts of TNF-alpha and MCP-1 in the serum, increased the number of total splenocytes and MHC class II+ CD11c+ leukocytes, and when combined with IFN-gamma, inhibited the progression of established Renca tumors in vivo in both wild-type and CD40-/- mice. Similarly, treatment of CD40+ A704 and ACHN human RCC lines with mouse anti-human CD40 Ab induced strong expression of genes and proteins for MCP-1, IL-8, and GM-CSF in vitro and in vivo. Finally, in SCID mice, the numbers of ACHN pulmonary metastases were dramatically reduced by treatment with species-specific human CD40 Ab. These results show that CD40 stimulation of CD40+ tumor cells can enhance immune responses and result in antitumor activity.
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http://dx.doi.org/10.4049/jimmunol.176.11.6543DOI Listing
June 2006

Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells.

Proc Natl Acad Sci U S A 2006 Apr 27;103(14):5460-5. Epub 2006 Mar 27.

Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV 89557, USA.

Naturally occurring CD4(+)CD25(+) T regulatory (Treg) cells have been shown to inhibit adaptive responses by T cells. Natural killer (NK) cells represent an important component of innate immunity in both cancer and infectious disease states. We investigated whether CD4(+)CD25(+) Treg cells could affect NK cell function in vivo by using allogeneic (full H2-disparate) bone marrow (BM) transplantation and the model of hybrid resistance, in which parental marrow grafts are rejected solely by the NK cells of irradiated (BALB/c x C57BL/6) F(1) recipients. We demonstrate that the prior removal of host Treg cells, but not CD8(+) T cells, significantly enhanced NK cell-mediated BM rejection in both models. The inhibitory role of Treg cells on NK cells was confirmed in vivo with adoptive transfer studies in which transferred CD4(+)CD25(+) cells could abrogate NK cell-mediated hybrid resistance. Anti-TGF-beta mAb treatment also increased NK cell-mediated BM graft rejection, suggesting that the NK cell suppression is exerted through TGF-beta. Thus, CD4(+)CD25(+) Treg cells can potently inhibit NK cell function in vivo, and their depletion may have therapeutic ramifications for NK cell function in BM transplantation and cancer therapy.
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http://dx.doi.org/10.1073/pnas.0509249103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459377PMC
April 2006

Peyer patches are not required for acute graft-versus-host disease after myeloablative conditioning and murine allogeneic bone marrow transplantation.

Blood 2006 Jan 13;107(1):410-2. Epub 2005 Sep 13.

Department of Microbiology and Immunology, University of Nevada School of Medicine, Mail Stop 199, Reno, NV 89557, USA.

Graft-versus-host disease (GVHD) is a multistep disease process following allogeneic bone marrow transplantation (BMT). It has been postulated that the induction of acute GVHD requires the presence of Peyer patches (PPs). A new tumor necrosis factor (TNF)-deficient strain has been developed that totally lacks PPs and displays the defects characteristic of TNF ablation but not lymphotoxin-associated defects characterized by lack of both PPs and lymph nodes. To determine the necessity of PPs in acute lethal GVHD induction, we transplanted full major histocompatibility complex (MHC)-mismatched grafts into myeloablated TNF knockout recipients. No differences in the survival or GVHD-associated histopathologic lesions were observed between the recipients. We conclude that neither PPs nor host TNF-alpha is required for the development of acute lethal GVHD in mice that undergo myeloablative conditioning and allogeneic BMT.
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http://dx.doi.org/10.1182/blood-2004-11-4565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895345PMC
January 2006

Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity.

Blood 2005 Nov 16;106(9):3293-9. Epub 2005 Jun 16.

Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA.

We have recently demonstrated that the proteasome inhibitor, bortezomib, administered immediately following murine allogeneic bone marrow transplantation (BMT) resulted in marked inhibition of acute graft-versus-host disease (GVHD) with retention of graft-versus-tumor effects. We now assessed the effects of delayed bortezomib administration (5 or more days after BMT) on GVHD. Recipient C57BL/6 (H2b) mice were lethally irradiated and given transplants of bone marrow cells and splenocytes from major histocompatibility complex (MHC)-disparate BALB/c (H2d) donors. In marked contrast to the effects of bortezomib on GVHD prevention when administered immediately after BMT, delayed bortezomib administration resulted in significant acceleration of GVHD-dependent morbidity. No toxicity was observed following delayed bortezomib administration in models where donor T cells were not coadministered, indicating that these deleterious effects were critically dependent on GVHD induction. The increase in GVHD susceptibility even occurred when late administration of bortezomib was preceded by early administration. Pathologic assessment revealed that significant increases in gastrointestinal lesions occurred following delayed bortezomib administration during GVHD. This pathology correlated with significant increases of type 1 tumor necrosis factor alpha (TNF-alpha) receptor transcription in gastrointestinal cells and with significant increases of TNF-alpha, interleukin 1beta (IL-1beta), and IL-6 levels in the serum. These results indicate that the differential effects of proteasome inhibition with bortezomib on GVHD are critically dependent on the timing of bortezomib administration.
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http://dx.doi.org/10.1182/blood-2004-11-4526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895334PMC
November 2005

Lack of correlation between an assay used to determine early marrow allograft rejection and long-term chimerism after murine allogeneic bone marrow transplantation: effects of marrow dose.

Biol Blood Marrow Transplant 2005 Apr;11(4):252-9

Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

The acute rejection of bone marrow (BM) allografts by host effectors can occur within a short period after BM transplantation (BMT) in lethally irradiated mice. Common assays used to ascertain engraftment/resistance involve measuring the growth of granulocyte/monocyte progenitors (colony-forming unit-granulocyte-macrophage) in vitro or splenocyte proliferation assessed by radioisotope incorporation in vivo 5 to 8 days after BMT. However, the correlation of the long-term outcome of BMT with the kinetics of recovery by using the dose of allogeneic BM cells (BMCs) that leads to early rejection as determined by the in vitro assessment has not been extensively studied. Thus, to investigate whether the early rejection of donor BMCs is an indication of a long-term engraftment failure, C57BL/6 (H2b) mice were lethally irradiated and transplanted with various doses of BALB/c (H2d) BMCs. The short-term engraftment of donor precursors (colony-forming unit-granulocyte-macrophage), the kinetics of hematopoietic cell recovery, the extent of donor chimerism, and the proportion of the recipients with long-term survival were determined. The results show that the kinetics and extent of hematopoietic cell recovery were significantly delayed in mice receiving limiting doses of BMCs that were rejected or severely resisted at day 8 after BMT. However, a proportion of these mice survived up to 98 days after BMT with mixed chimerism or donor chimerism. This study demonstrates that early rejection of BM precursors, as assessed by measurement of myeloid progenitors in the spleen after BMT, does not always correlate with the long-term outcome of the marrow allograft and that significant variability is inherent in the extent of chimerism when threshold amounts of BMCs are used.
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http://dx.doi.org/10.1016/j.bbmt.2005.01.006DOI Listing
April 2005

Tumor regression by anti-CD40 and interleukin-2: role of CD40 in hematopoietic cells and organ-specific effects.

Biol Blood Marrow Transplant 2004 Aug;10(8):534-9

Department of Microbiology and Immunology, University of Nevada, Reno, Nevada 89557, USA.

CD40 stimulation can synergize with interleukin (IL)-2 for antitumor responses against mouse metastatic renal cell carcinomas, with coincident increases in tumor-specific CD8+ T-cell responses and dendritic cell numbers in both the spleen and liver. Because CD40 is present on various hematopoietic-derived cells, endothelial cells, and some tumors themselves, this study was performed to determine whether the antitumor effects of CD40 stimulation and IL-2 were primarily mediated by CD40+ hematopoietic-derived cells. Bone marrow chimeras were created by reconstituting lethally irradiated CD40+/+ recipients with bone marrow from CD40-/- or CD40+/+ mice. Chimeric mice were then implanted orthotopically with renal cancer cells, followed by treatment with anti-CD40 agonist monoclonal antibodies and IL-2. Immune parameters of the spleen and liver were assessed after therapy and correlated with antitumor responses. The antitumor effects in the CD40-/- bone marrow transplantation chimeras were almost completely abrogated after treatment, and this shows that hematopoietically derived CD40+ cells are the principal targets for CD40 stimulation in this model. Although both spleen and liver showed reductions in CD8+ T-cell and dendritic cell expansion in the CD40-/- versus CD40+/+ chimeras after therapy, only the liver exhibited no significant increases in either CD8+ T cells or dendritic cells after treatment. CD40 cells on hematopoietic cells are the primary target for anti-CD40 and IL-2 therapy. The results also suggest that the immunologic events in the liver may be more revealing that those in lymphoid organs with regard to critical events related to responses after therapy.
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http://dx.doi.org/10.1016/j.bbmt.2004.05.006DOI Listing
August 2004

Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.

Proc Natl Acad Sci U S A 2004 May 17;101(21):8120-5. Epub 2004 May 17.

Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA.

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer.
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http://dx.doi.org/10.1073/pnas.0401563101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419567PMC
May 2004

An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease.

Exp Hematol 2004 Mar;32(3):318-24

Department of Microbiology and Immunology, University of Nevada, Reno, Nev. 89557, USA.

Objective: Chemokines have been postulated to play a role in the pathogenesis of graft-vs-host disease (GVHD) after allogeneic hematopoietic transplantation. Recent reports have indicated that the absence of donor expression of CCR5 on T cells ameliorates GVHD in models using no conditioning of the recipient. We therefore assessed the role of CCR5 on donor cells in models where intensive conditioning of the recipient occurs, thus more appropriately mirroring the clinical experience.

Methods: Lethally irradiated mice received allogeneic bone marrow transplants. Recipients were given full MHC-mismatched donor bone marrow and splenocytes from CCR5 knockout (KO) mice vs wild-type (WT) control donors.

Results: Recipients of CCR5 KO donor cells succumbed to acute GVHD at an accelerated rate compared to mice receiving WT cells. Donor CD8+ T cells expanded to a significantly greater extent in recipients of CCR5 KO vs WT control cells. T cells recovered from recipients of CCR5 KO cells produced more IFN-gamma and TNF-alpha and proliferated to a T-cell mitogen at a significantly greater level then T cells from recipients of WT cells, indicating that CCR5 plays a role in downregulating donor alloreactive CD8+ T-cell expansion. Histological assessment of the mice indicated pathological lesions in the kidneys and a greater degree of liver pathological changes in mice that received CCR5 KO donor grafts.

Conclusions: These results indicate that the role of CCR5 in allogeneic bone marrow transplants and GVHD is more complex than initially thought. In a murine transplant model with intensive conditioning, the overall effect of absent CCR5 expression on donor cells results in greater GVHD and donor T-cell expansion.
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http://dx.doi.org/10.1016/j.exphem.2003.12.003DOI Listing
March 2004

Effects of organ-specific loss of insulin-like growth factor-I production on murine hematopoiesis.

Biol Blood Marrow Transplant 2004 Jan;10(1):32-9

Department of Microbiology & Immunology, University of Nevada School of Medicine, Reno 89557, USA.

To determine whether circulating insulin-like growth factor (IGF)-I has a role in hematopoiesis, we examined hematologic parameters in mice with markedly reduced serum levels resulting from a liver-specific inactivation of the IGF-I gene. These mice have normal postnatal growth and development, suggesting that local production of IGF-I can maintain anabolic effects. Liver-specific IGF-I-deficient (LID) mice were compared with control littermates with regard to hematopoietic parameters. Spleen cellularity was decreased in the LID mice compared with control mice. Spleen myeloid progenitors, as determined by colony-forming units-granulocyte/monocyte (CFU-GM) and colony-forming units-high proliferative potential (CFU-HPP), were significantly decreased in the LID mice. Immune parameters, as indicated by the absolute number of B and T cells, did not significantly differ between the knockout and control mice. In contrast to the decreased cellularity and myelopoiesis in the spleen, bone marrow cellularity was not different between the 2 groups, but the total femoral content of CFU-GM and CFU-HPP was significantly increased in the LID mice. The decrease in splenic myelopoiesis was not due to the inability of progenitors to exit the bone marrow, because CFU-GM and burst-forming units-erythroid were significantly increased in the blood of LID mice compared with normal littermates. Administration of exogenous IGF-I to the LID mice for 4 days partially restored myelopoietic parameters in the spleen. Liver production of IGF-I and, therefore, normal serum levels of this hormone, although not necessary for general organ growth and development, seems necessary for survival or transition of myeloid progenitors into the spleen.
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http://dx.doi.org/10.1016/j.bbmt.2003.09.008DOI Listing
January 2004

Immunologic and hematopoietic effects of recombinant human prolactin after syngeneic bone marrow transplantation in mice.

Biol Blood Marrow Transplant 2003 Jul;9(7):426-34

School of Life Sciences, University of Sciences and Technology of China, Anhui, China.

The period of immune deficiency following bone marrow transplantation (BMT) results in a susceptibility to opportunistic infections and remains a growing obstacle in improving the efficacy of BMT. Neuroendocrine hormones have been shown to affect numerous immunologic and hematologic responses after in vivo administration. We investigated whether neuroendocrine hormones, notably prolactin (PRL), could be administered after BMT and result in improved immunologic recovery. Mice were given lethal total body irradiation followed with a congeneic or a syngeneic BMT. Some groups then received recombinant human PRL (rhPRL) daily for 3 weeks. Effects on immune reconstitution and function were then monitored. The results show that PRL could increase thymic cellularity and donor T-cell reconstitution after congeneic BMT. Increases in B cells and myeloid progenitors were also observed. Mitogenic responses by both T and B cells were observed after PRL treatment. These results suggest that PRL may be of use to promote immune and myeloid reconstitution after BMT.
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http://dx.doi.org/10.1016/s1083-8791(03)00107-1DOI Listing
July 2003

Expansion of LTC-ICs and maintenance of p21 and BCL-2 expression in cord blood CD34(+)/CD38(-) early progenitors cultured over human MSCs as a feeder layer.

Stem Cells 2002 ;20(6):573-82

Department of Medicine, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, Ohio 44106-5061, USA.

Allogeneic transplantation with umbilical cord blood (UCB) is limited in adult recipients by a low CD34(+) cell dose. Clinical trials incorporating cytokine-based UCB in vitro expansion have not demonstrated significant shortening of hematologic recovery despite substantial increases in CD34(+) cell dose, suggesting loss of stem cell function. To sustain stem cell function during cytokine-based in vitro expansion, a feeder layer of human mesenchymal stem cells (MSCs) was incorporated in an attempt to mimic the stem cell niche in the marrow microenvironment. UCB expansion on MSCs resulted in a 7.7-fold increase in total LTC-IC output and a 3.8-fold increase of total early CD34(+) progenitors (CD38(-)/HLA-DR(-)). Importantly, early CD34(+)/CD38(-)/HLA-DR(-) progenitors from cultures expanded on MSCs demonstrated higher cytoplasmic expression of the cell-cycle inhibitor, p21(cip1/waf1), and the antiapoptotic protein, BCL-2, compared with UCB expanded in cytokines alone, suggesting improved maintenance of stem cell function in the presence of MSCs. Moreover, the presence of MSCs did not elicit UCB lymphocyte activation. Taken together, these results strongly suggest that the addition of MSCs as a feeder layer provides improved conditions for expansion of early UCB CD34(+)/CD38(-)/HLA-DR(-) hematopoietic progenitors and may serve to inhibit their differentiation and rates of apoptosis during short-term in vitro expansion.
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http://dx.doi.org/10.1634/stemcells.20-6-573DOI Listing
May 2003