Publications by authors named "Stewart Sell"

55 Publications

CD25-Targeted IL-2 Signals Promote Improved Outcomes of Influenza Infection and Boost Memory CD4 T Cell Formation.

J Immunol 2020 06 6;204(12):3307-3314. Epub 2020 May 6.

Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827;

IL-2 is a pleotropic cytokine with potent pro- and anti-inflammatory effects. These divergent impacts can be directed in vivo by forming complexes of IL-2 and anti-IL-2 mAbs (IL-2C) to target IL-2 to distinct subsets of cells based on their expression of subunits of the IL-2R. In this study, we show that treatment of mice with a prototypical anti-inflammatory IL-2C, JES6-1-IL-2C, best known to induce CD25 regulatory CD4 T cell expansion, surprisingly causes robust induction of a suite of inflammatory factors. However, treating mice infected with influenza A virus with this IL-2C reduces lung immunopathology. We compare the spectrum of inflammatory proteins upregulated by pro- and anti-inflammatory IL-2C treatment and uncover a pattern of expression that reveals potentially beneficial versus detrimental aspects of the influenza-associated cytokine storm. Moreover, we show that anti-inflammatory IL-2C can deliver survival signals to CD4 T cells responding to influenza A virus that improve their memory fitness, indicating a novel application of IL-2 to boost pathogen-specific T cell memory while simultaneously reducing immunopathology.
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http://dx.doi.org/10.4049/jimmunol.2000205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327712PMC
June 2020

Proximal Tubular Vacuolization and Hypersensitivity to Drug-Induced Nephrotoxicity in Male Mice With Decreased Expression of the NADPH-Cytochrome P450 Reductase.

Toxicol Sci 2020 02;173(2):362-372

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona.

The effect of variations in the expression of cytochrome P450 reductase (CPR or POR) is determined in mice with decreased POR expression to identify potential vulnerabilities in people with low POR expression. There is an age-dependent appearance of increasing vacuolization in the proximal tubules of the renal cortex in 4- to 9-month-old male (but not female) Cpr-low (CL) mice. These mice have low POR expression in all cells of the body and upregulation of lysosome-associated membrane protein 1 expression in the renal cortex. Vacuolization is also seen in extrahepatic CL and extrarenal CL male mice, but not in mice with tissue-specific Por deletion in liver, intestinal epithelium, or kidney. The occurrence of vacuolization is accompanied by increases in serum blood-urea-nitrogen levels. Male CL mice are hypersensitive to cisplatin- and gentamicin-induced renal toxicity at 3 months of age, before proximal tubular (PT) vacuoles are detectable. At doses that do not cause renal toxicity in wild-type mice, both drugs cause substantial increases in serum blood-urea-nitrogen levels and PT vacuolization in male but not female CL mice. The hypersensitivity to drug-induced renal toxicity is accompanied by increases in circulating drug levels. These novel findings demonstrate deficiency of renal function in mice with globally reduced POR expression and suggest that low POR expression may be a risk factor for drug-induced nephrotoxicity in humans.
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http://dx.doi.org/10.1093/toxsci/kfz225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000068PMC
February 2020

How vaccines work: immune effector mechanisms and designer vaccines.

Authors:
Stewart Sell

Expert Rev Vaccines 2019 10;18(10):993-1015

Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA.

: Three major advances have led to increase in length and quality of human life: increased food production, improved sanitation and induction of specific adaptive immune responses to infectious agents (vaccination). Which has had the most impact is subject to debate. The number and variety of infections agents and the mechanisms that they have evolved to allow them to colonize humans remained mysterious and confusing until the last 50 years. Since then science has developed complex and largely successful ways to immunize against many of these infections.: Six specific immune defense mechanisms have been identified. neutralization, cytolytic, immune complex, anaphylactic, T-cytotoxicity, and delayed hypersensitivity. The role of each of these immune effector mechanisms in immune responses induced by vaccination against specific infectious agents is the subject of this review.: In the past development of specific vaccines for infections agents was largely by trial and error. With an understanding of the natural history of an infection and the effective immune response to it, one can select the method of vaccination that will elicit the appropriate immune effector mechanisms (designer vaccines). These may act to prevent infection (prevention) or eliminate an established on ongoing infection (therapeutic).: The primary literature source is Pub Med. Secondary source is Wikipedia.
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http://dx.doi.org/10.1080/14760584.2019.1674144DOI Listing
October 2019

Comparison of survivor scores for differentiation therapy of cancer to those for checkpoint inhibition: Half full or half empty.

Tumour Biol 2019 Sep;41(9):1010428319873749

Division of Translational Medicine, Wadsworth Center, New York State Department of Health, Albany, NY, USA.

Differentiation therapy is directed to the self-renewing cancer stem cells, as well as their progeny transit amplifying cells, to force them to mature to terminal differentiation. Differentiation therapy is effective in treatment of neuroblastomas and myeloid leukemias. Checkpoint inhibition therapy removes blocks to cancer reactive T-killer cells and allows them to react to malignant cells and limit the growth of cancer. The percentage of patients with a given cancer that responds to either therapy is less than hoped for, and the duration of response is variable. Multiplying the response rate (percentage of patients responding to therapy) by the duration of response may be used to derive a survival score for patients treated with differentiation therapy or checkpoint inhibition. By this criterion, differentiation therapy gives better survival scores than checkpoint inhibition. Yet, checkpoint inhibition is considered a great success, mostly because it may be applied to many different types of cancer, and differentiation therapy is considered relatively ineffective because it is limited to a few specific cancers. On the other hand, the cost of checkpoint inhibition treatment is 10-20 times more per patient than that of differentiation therapy. Hopefully, future combined treatments and advances in both approaches will increase the effectiveness of these cancer treatments.
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http://dx.doi.org/10.1177/1010428319873749DOI Listing
September 2019

Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation.

PLoS Pathog 2019 08 14;15(8):e1007989. Epub 2019 Aug 14.

Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.

Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals to reduce CD4 T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 T cells and improves the outcome of IAV infection in vaccinated mice. Finally, we show that IL-2 administration drives rapid and extremely potent lung inflammation involving NK cells, which can synergize with sublethal IAV infection to promote acute death. These results suggest that IL-2 production is not necessarily an indicator of protective CD4 T cells, and that the lung environment is particularly sensitive to IL-2-induced inflammation during viral infection.
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http://dx.doi.org/10.1371/journal.ppat.1007989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693742PMC
August 2019

T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming.

Mucosal Immunol 2019 09 5;12(5):1220-1230. Epub 2019 Jul 5.

Burnett School of Biomedical Sciences, Division of Immunity and Pathogenesis, College of Medicine, University of Central Florida, Orlando, FL, USA.

Although clearance of many intracellular pathogens requires T-bet-dependent CD4 T cell programming, the extent to which T-bet is needed to direct protective CD4 responses against influenza is not known. Here, we characterize wild-type and T-bet-deficient CD4 cells during murine influenza infection. Surprisingly, although T-bet expression has broad impacts on cytokine production by virus-specific CD4 cells, the protective efficacy of T-bet-deficient effector cells is only marginally reduced. This reduction is due to lower CXCR3 expression, leading to suboptimal accumulation of activated T-bet-deficient cells in the infected lung. However, T-bet-deficient cells outcompete wild-type cells to form lung-resident and circulating memory populations following viral clearance, and primed T-bet-deficient mice efficiently clear supralethal heterosubtypic influenza challenges even when depleted of CD8 T cells. These results are relevant to the identification of more incisive correlates of protective T cells and for vaccines that aim to induce durable cellular immunity against influenza.
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http://dx.doi.org/10.1038/s41385-019-0183-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717559PMC
September 2019

Mouse Models Reveal Role of T-Cytotoxic and T-Reg Cells in Immune Response to Influenza: Implications for Vaccine Design.

Viruses 2019 01 11;11(1). Epub 2019 Jan 11.

Burnett School of Biomedical Sciences, University of Central Florida Medical School, Orlando, FL 32816, USA.

Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung with T-cells. This is followed by invasion of T-cells into the bronchiolar epithelium, and separation of epithelial cells from each other and from the basement membrane leading to defoliation of the bronchial epithelium. The intraepithelial reaction may involve either CD8 or CD4 T-cytotoxic cells and is analogous to a viral exanthema of the skin, such as measles and smallpox, which occur when the immune response against these infections is activated and the infected cells are attacked by T-cytotoxic cells. Then there is formation of B-cell follicles adjacent to bronchi, i.e., induced bronchial associated lymphoid tissue (iBALT). iBALT reacts like the cortex of a lymph node and is a site for a local immune response not only to the original viral infection, but also related viral infections (heterologous immunity). Proliferation of Type II pneumocytes and/or terminal bronchial epithelial cells may extend into the adjacent lung leading to large zones filled with tumor-like epithelial cells. The effective killing of influenza virus infected epithelial cells by T-cytotoxic cells and induction of iBALT suggests that adding the induction of these components might greatly increase the efficacy of influenza vaccination.
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http://dx.doi.org/10.3390/v11010052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356589PMC
January 2019

Participation of liver stem cells in cholangiocarcinogenesis after aflatoxin B exposure of glutathione S-transferase A3 knockout mice.

Tumour Biol 2018 May;40(5):1010428318777344

1 Wadsworth Center, New York State Department of Health, Albany, NY, USA.

Aflatoxin B, arguably the most potent human carcinogen, induces liver cancer in humans, rats, trout, ducks, and so on, but adult mice are totally resistant. This resistance is because of a detoxifying enzyme, mouse glutathione S-transferase A3, which binds to and inactivates aflatoxin B epoxide, preventing the epoxide from binding to DNA and causing mutations. Glutathione S-transferase A3 or its analog has not been detected in any of the sensitive species, including humans. The generation of a glutathione S-transferase A3 knockout (represented as KO or -/-) mice has allowed us to study the induction of liver cancer in mice by aflatoxin B. In contrast to the induction of hepatocellular carcinomas in other species, aflatoxin B induces cholangiocarcinomas in GSTA3-/- mice. In other species and in knockout mice, the induction of liver cancer is preceded by extensive proliferation of small oval cells, providing additional evidence that oval cells are bipolar stem cells and may give rise to either hepatocellular carcinoma or cholangiocarcinoma depending on the nature of the hepatocarcinogen and the species of animal. The recent development of mouse oval cell lines in our laboratory from aflatoxin B-treated GSTA3-/- mice should provide a new venue for study of the properties and potential of putative mouse liver stem cells.
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http://dx.doi.org/10.1177/1010428318777344DOI Listing
May 2018

Cancer immunotherapy: Breakthrough or "deja vu, all over again"?

Authors:
Stewart Sell

Tumour Biol 2017 Jun;39(6):1010428317707764

Wadsworth Center, New York State Department of Health and Albany College of Pharmacy and Health Sciences, Albany, NY, USA.

From the application of Coley's toxin in the early 1900s to the present clinical trials using immune checkpoint regulatory inhibitors, the history of cancer immunotherapy has consisted of extremely high levels of enthusiasm after anecdotal case reports of enormous success, followed by decreasing levels of enthusiasm as the results of controlled clinical trials are available. In this review, this pattern will be documented for the various immunotherapeutic approaches over the years. The sole exception being vaccination against cancer causing viruses, which have already prevented thousands of cancers. We can only hope that the present high level of enthusiasm for the use of immune stimulation by removal of blocks to cancer immunity will be more productive than the incremental improvements using previous immunotherapies.
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http://dx.doi.org/10.1177/1010428317707764DOI Listing
June 2017

Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice.

Carcinogenesis 2017 07;38(7):717-727

Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA.

We recently generated glutathione S-transferase (GST) A3 knockout (KO) mice as a novel model to study the risk factors for liver cancer. GSTA3 KO mice are sensitive to the acute cytotoxic and genotoxic effects of aflatoxin B1 (AFB1), confirming the crucial role of GSTA3 in resistance to AFB1. We now report histopathological changes, tumor formation, biochemical changes and gender response following AFB1 treatment as well as the contribution of oxidative stress. Using a protocol of weekly 0.5 mg AFB1/kg administration, we observed extensive oval (liver stem) cell (OC) proliferation within 1-3 weeks followed by microvesicular lipidosis, megahepatocytes, nuclear inclusions, cholangiomas and small nodules. Male and female GSTA3 KO mice treated with 12 and 24 weekly AFB1 injections followed by a rest period of 12 and 6 months, respectively, all had grossly distorted livers with macro- and microscopic cysts, hepatocellular nodules, cholangiomas and cholangiocarcinomas and OC proliferation. We postulate that the prolonged AFB1 treatment leads to inhibition of hepatocyte proliferation, which is compensated by OC proliferation and eventually formation of cholangiocarcinoma (CCA). At low-dose AFB1, male KO mice showed less extensive acute liver injury, OC proliferation and AFB1-DNA adducts than female KO mice. There were no significant compensatory changes in KO mice GST subunits, GST enzymatic activity, epoxide hydrolase, or CYP1A2 and CYP3A11 levels. Finally, there was a modest increase in F2-isoprostane and isofuran in KO mice that confirmed putative GSTA3 hydroperoxidase activity in vivo for the first time.
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http://dx.doi.org/10.1093/carcin/bgx048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862260PMC
July 2017

Downregulation of Bmi1 in breast cancer stem cells suppresses tumor growth and proliferation.

Oncotarget 2017 Jun;8(24):38731-38742

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.

Targeting cancer stem cells during initial treatment is important to reduce incidence of recurrent disease. Bmi1 has been associated with cancer stem cell self-renewal and aggressive disease. The purpose of this study was to determine the effects of downregulation of Bmi1 in breast cancer stem cells in order to target and eliminate the stem cell population in the tumor mass. Bmi1 was downregulated using two approaches in the mouse breast cancer stem cell line FMMC 419II-a small molecule inhibitor (PTC 209) and stable transfection with a Bmi1 shRNA plasmid. The functional effect of Bmi1 downregulation was tested in vitro and in vivo. Each approach led to decreased Bmi1 expression that correlated with an inhibition of cancer stem cell properties in vitro including cell cycle arrest and reduced mammosphere forming potential, and a decrease in tumor mass in vivo after either intra-tumoral or systemic nanoparticle-targeted delivery of anti-Bmi1. These results show that inhibiting Bmi1 expression in breast cancer stem cells could be important for the complete elimination of tumor and potentially preventing disease relapse.
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http://dx.doi.org/10.18632/oncotarget.16317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503567PMC
June 2017

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts.

Horm Cancer 2017 06 10;8(3):157-165. Epub 2017 Apr 10.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, 12144, USA.

Thyroid hormone as L-thyroxine (T) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.
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http://dx.doi.org/10.1007/s12672-017-0293-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413536PMC
June 2017

Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza.

J Immunol 2016 10 19;197(8):3260-3270. Epub 2016 Sep 19.

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; and.

Memory T cells can often respond against pathogens that have evaded neutralizing Abs and are thus key to vaccine-induced protection, yet the signals needed to optimize their responses are unclear. In this study, we identify a dramatic and selective requirement for IL-6 to achieve optimal memory CD4 T cell recall following heterosubtypic influenza A virus (IAV) challenge of mice primed previously with wild-type or attenuated IAV strains. Through analysis of endogenous T cell responses and adoptive transfer of IAV-specific memory T cell populations, we find that without IL-6, CD4, but not CD8, secondary effector populations expand less and have blunted function and antiviral impact. Early and direct IL-6 signals to memory CD4 T cells are required to program maximal secondary effector responses at the site of infection during heterosubtypic challenge, indicating a novel role for a costimulatory cytokine in recall responses.
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http://dx.doi.org/10.4049/jimmunol.1600033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101150PMC
October 2016

Origin of the stem cell niche concept.

Exp Hematol 2016 09 8;44(9):809-810. Epub 2016 Jul 8.

Wadsworth Laboratories, New York State Department of Health, Albany, New York. Electronic address:

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http://dx.doi.org/10.1016/j.exphem.2016.05.016DOI Listing
September 2016

Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells.

Oncotarget 2016 Aug;7(31):50365-50379

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.

High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line's sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment.
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http://dx.doi.org/10.18632/oncotarget.10395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226588PMC
August 2016

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and "early aging" mice.

Aging (Albany NY) 2015 Dec;7(12):1212-23

Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA.

Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16-18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712343PMC
http://dx.doi.org/10.18632/aging.100867DOI Listing
December 2015

Immunopathology of Experimental Models of Syphilis, Influenza, and Asthma.

Authors:
Stewart Sell

For Immunopathol Dis Therap 2016 ;7(3-4):225-236

Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, 12201; Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue Albany, NY, 12208; Division of Biological Sciences, University at Albany, 1400 Washington Avenue, Albany, NY, 12222.

The introduction of immunopathologic reaction classification in the 1960s led to a major advance in understanding immune effector mechanisms and how lesions of immunopathologic diseases developed. In this article, immunopathologic mechanisms are presented for experimental models of syphilis, influenza, and asthma. The chancre of syphilis is a delayed hypersensitivity skin reaction that is initiated by sensitized T cells that activate macrophages to phagocytose and kill the infecting organism, , in interstitial tissues. The primary immune effector mechanism in experimental influenza is T-cell-mediated cytotoxicity that kills infected epithelial cells, bronchial lining cells, and Type-II pneumocytes, in a manner similar to viral exanthema. The bronchial lesions of the experimental model of asthma in mice are preceded by an immune complex vasculitis and not an immunoglobulin E-mediated mast cell mechanism.
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http://dx.doi.org/10.1615/ForumImmunDisTher.2017020136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985826PMC
January 2016

Cancer: A Problem of Developmental Biology; Scientific Evidence for Reprogramming and Differentiation Therapy.

Curr Drug Targets 2016 ;17(10):1103-10

Scientific Institute of Research and Care Multimedica, Milan, Italy.

Current medical literature acknowledges that embryonic micro-environment is able to suppress tumor development. Administering carcinogenic substances during organogenesis in fact leads to embryonic malformations, but not to offspring tumor growth. Once organogenesis has ended, administration of carcinogenic substances causes a rise in offspring tumor development. These data indicate that cancer can be considered a deviation in normal development, which can be regulated by factors of the embryonic microenvironment. Furthermore, it has been demonstrated that teratoma differentiates into normal tissues once it is implanted in the embryo. Recently, it has been shown that implanting a melanoma in Zebrafish embryo did not result in a tumor development; however, it did in the adult specimen. This demonstrates that cancer cells can differentiate into normal tissues when implanted in the embryo. In addition, it was demonstrated that other tumors can revert into a normal phenotype and/or differentiate into normal tissue when implanted in the embryo. These studies led some authors to define cancer as a problem of developmental biology and to predict the present concept of "cancer stem cells theory". In this review, we record the most important researches about the reprogramming and differentiation treatments of cancer cells to better clarify how the substances taken from developing embryo or other biological substances can induce differentiation of malignant cells. Lastly, a model of cancer has been proposed here, conceived by one of us, which is consistent with the reality, as demonstrated by a great number of researches. This model integrates the theory of the "maturation arrest" of cancer cells as conceived by B. Pierce with the theory which describes cancer as a process of deterministic chaos determined by genetic and/or epigenetic alterations in differentiated cells, which leads a normal cell to become cancerous. All the researches here described demonstrated that cancer can be considered a problem of developmental biology and that one of the most important hallmarks of cancer is the loss of differentiation as already described by us in other articles.
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http://dx.doi.org/10.2174/1389450116666150907102717DOI Listing
August 2017

Bronchial lesions of mouse model of asthma are preceded by immune complex vasculitis and induced bronchial associated lymphoid tissue (iBALT).

Lab Invest 2015 Aug 1;95(8):886-902. Epub 2015 Jun 1.

1] Division of Translational Medicine, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA [2] School of Public Health, University at Albany, Albany, NY, USA.

We systematically examined by immune histology the lungs of some widely used mouse models of asthma. These models include sensitization by multiple intraperitoneal injections of soluble ovalbumin (OVA) or of OVA with alum, followed by three intranasal or aerosol challenges 3 days apart. Within 24 h after a single challenge there is fibrinoid necrosis of arterial walls with deposition of immunoglobulin (Ig) and OVA and infiltration of eosinophilic polymorphonuclear cells that lasts for about 3 days followed by peribronchial B-cell infiltration and slight reversible goblet cell hypertrophy (GCHT). After two challenges, severe eosinophilic vasculitis is present at 6 h, increases by 72 h, and then declines; B-cell proliferation and significant GCHT and hyperplasia (GCHTH) and bronchial smooth muscle hypertrophy recur more prominently. After three challenges, there is significantly increased induced bronchus-associated lymphoid tissue (iBALT) formation, GCHTH, and smooth muscle hypertrophy. Elevated levels of Th2 cytokines, IL-4, IL-5, and IL-13, are present in bronchial lavage fluids. Sensitized mice have precipitating antibody and positive Arthus skin reactions but also develop significant levels of IgE antibody to OVA but only 1 week after challenge. We conclude that the asthma like lung lesions induced in these models is preceded by immune complex-mediated eosinophilic vasculitis and iBALT formation. There are elevations of Th2 cytokines that most likely produce bronchial lesions that resemble human asthma. However, it is unlikely that mast cell-activated atopic mechanisms are responsible as we found only a few presumed mast cells by toluidine blue and metachromatic staining limited to the most proximal part of the main stem bronchus, and none in the remaining main stem bronchus or in the lung periphery.
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http://dx.doi.org/10.1038/labinvest.2015.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520747PMC
August 2015

Suppression of pulmonary CYP2A13 expression by carcinogen-induced lung tumorigenesis in a CYP2A13-humanized mouse model.

Drug Metab Dispos 2015 May 20;43(5):698-702. Epub 2015 Feb 20.

Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)

CYP2A13 is a human cytochrome P450 (P450) enzyme important in the bioactivation of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). CYP2A13 expression levels vary dramatically among lung biopsy samples from patients, presumably owing in part to a suppression of CYP2A13 expression by disease-associated inflammation. Here, we determined whether CYP2A13 expression in the lungs of CYP2A13-humanized mice is suppressed by the presence of lung tumors. Tissues from an NNK lung tumor bioassay were examined. CYP2A13-humanized mice (95-100%) had multiple lung tumors at 16 weeks after NNK (30 or 50 mg/kg) treatment; whereas only ∼9% of saline-treated CYP2A13-humanized mice had lung tumor (∼1/lung). Mice with lung tumors, from the NNK-treated groups, were used for dissecting adjacent tumor-free lung tissues; whereas mice without visible lung tumors, from the saline-treated group, were used as controls. Compared with the controls, the levels of CYP2A13 protein and mRNA were both reduced significantly (by ≥50%) in the NNK-treated groups. The levels of mouse CYP2B10 and CYP2F2 mRNAs were also significantly lower in the dissected normal lung tissues from tumor-bearing mice than in lungs from the control mice. Pulmonary tissue levels of three proinflammatory cytokines, tumor necrosis factor alpha, interferon gamma, and interleukin-6, were significantly higher in the tumor-bearing mice than in the controls, indicating occurrence of low-grade lung inflammation at the time of necropsy. Taken together, these findings support the hypothesis that CYP2A13 levels in human lungs can be suppressed by disease-associated inflammation in tissue donors, a scenario causing underestimation of CYP2A13 levels in healthy lungs.
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http://dx.doi.org/10.1124/dmd.115.063305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407704PMC
May 2015

Intraepithelial T-cell cytotoxicity, induced bronchus-associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza.

Viral Immunol 2014 Dec;27(10):484-96

1 New York State Department of Health, Wadsworth Center , Albany, New York.

Immunopathologic examination of the lungs of mice with experimental influenza virus infection reveals three prominent findings. (i) There is rapidly developing perivascular (arterial) and peribronchial infiltration with T-cells and invasion of T-cells into the bronchiolar epithelium, separation of epithelial cells from each other and from the basement membrane, leading to defoliation of the bronchial epithelium. This reaction is analogous to a viral exanthema of the skin, such as measles and smallpox. This previously described but unappreciated reaction most likely is an effective way to eliminate virus-infected cells, but may contribute to acute toxicity and mortality. (ii) After this, there is formation of dense collections of lymphocytes adjacent to bronchi consisting mainly of B-cells, with a scattering of T-cells and macrophages. This is known as induced bronchial-associated lymphoid tissue (iBALT) and correlates with increased interleukin (IL)-17 in the lung. iBALT provides sites for a local immune reaction in the lung to both the original infection and related viral infections (heterologous immunity). (iii) Within the first 2-3 weeks, there is proliferation of type II pneumocytes and/or terminal bronchial epithelial cells extending from the terminal bronchioles into the adjacent alveoli, eventually leading to large zones of the lung filled with tumor-like epithelial cells with squamous metaplasia. The proliferation correlates with IL-17 and IL-22 expression, and the extent of this reaction appears to be determined by the availability of T-regulatory cells.
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http://dx.doi.org/10.1089/vim.2014.0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259197PMC
December 2014

Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer.

Toxicol Appl Pharmacol 2015 Jan 4;282(1):30-41. Epub 2014 Nov 4.

Wadsworth Center, New York State Department of Health, Albany, NY 12201, United States; Department of Environmental Health Sciences, School of Public Health, University at Albany, State University of New York, Albany, NY 12201, United States. Electronic address:

The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n=2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n=4>5≫2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility.
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http://dx.doi.org/10.1016/j.taap.2014.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404625PMC
January 2015

Genetic or pharmacologic activation of Nrf2 signaling fails to protect against aflatoxin genotoxicity in hypersensitive GSTA3 knockout mice.

Toxicol Sci 2014 Jun 27;139(2):293-300. Epub 2014 Mar 27.

Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, Maryland 21205.

Mice are resistant to aflatoxin hepatotoxicity, primarily due to high expression of glutathione S-transferases (GSTs), and in particular the GSTA3 subunit. Nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, which controls a broad-based cytoprotective response, was activated either genetically or pharmacologically in an attempt to rescue GSTA3 knockout mice from aflatoxin genotoxicity. Genetic activation of Nrf2 signaling was attained in a GSTA3: hepatocyte-specific Keap1 double knockout (DKO) mouse whereas pharmacologic activation of Nrf2 was achieved through pretreatment of mice with the triterpenoid 1-[2-cyano-3-,12-dioxoleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) prior to aflatoxin B1 exposure. Following oral treatment with aflatoxin, urine was collected from mice for 24 h and hepatic and urinary aflatoxin metabolites then quantified using isotope dilution-mass spectrometry. Although Nrf2 was successfully activated genetically and pharmacologically, neither means affected the response of GSTA3 knockout mice to chemical insult with aflatoxin. Hepatic aflatoxin B1-N(7)-guanine levels were elevated 120-fold in GSTA3 knockout mice compared with wild-type and levels were not attenuated by the interventions. This lack of effect was mirrored in the urinary excretion of aflatoxin B1-N(7)-guanine. By contrast, urinary excretion of aflatoxin B1-N-acetylcysteine was >200-fold higher in wild-type mice compared with the single GSTA3 knockout or DKO mouse. The inability to rescue GSTA3 knockout mice from aflatoxin genotoxicity through the Nrf2 transcriptional program indicates that Gsta3 is unilaterally responsible for the detoxication of aflatoxin in mice.
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http://dx.doi.org/10.1093/toxsci/kfu056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064015PMC
June 2014

Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection.

J Immunol 2013 Apr 6;190(7):3438-46. Epub 2013 Mar 6.

Trudeau Institute, Saranac Lake, NY 12983, USA.

Regulatory CD4(+)Foxp3(+) T cells (Tregs) are key regulators of inflammatory responses and control the magnitude of cellular immune responses to viral infections. However, little is known about how Tregs contribute to immune regulation during memory responses to previously encountered pathogens. In this study, we used MHC class II tetramers specific for the 311-325 peptide from influenza nucleoprotein (NP311-325/IA(b)) to track the Ag-specific Treg response to primary and secondary influenza virus infections. During secondary infections, Ag-specific memory Tregs showed accelerated accumulation in the lung-draining lymph node and lung parenchyma relative to a primary infection. Memory Tregs effectively controlled the in vitro proliferation of memory CD8(+) cells in an Ag-specific fashion that was MHC class II dependent. When memory Tregs were depleted before secondary infection, the magnitude of the Ag-specific memory CD8(+) T cell response was increased, as was pulmonary inflammation and airway cytokine/chemokine expression. Replacement of memory Tregs with naive Tregs failed to restore the regulation of the memory CD8 T cell response during secondary infection. Together, these data demonstrate the existence of a previously undescribed population of Ag-specific memory Tregs that shape the cellular immune response to secondary influenza virus challenges and offer an additional parameter to consider when determining the efficacy of vaccinations.
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http://dx.doi.org/10.4049/jimmunol.1203140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608733PMC
April 2013

Characterization of mammary cancer stem cells in the MMTV-PyMT mouse model.

Tumour Biol 2012 Dec 10;33(6):1983-96. Epub 2012 Aug 10.

Translational and Functional Genomics Laboratory, Ordway Research Institute, Albany, NY 12208, USA.

Breast cancer stem cells, the root of tumor growth, present challenges to investigate: Primary human breast cancer cells are difficult to establish in culture and inconsistently yield tumors after transplantation into immune-deficient recipient mice. Furthermore, there is limited characterization of mammary cancer stem cells in mice, the ideal model for the study of breast cancer. We herein describe a pre-clinical breast cancer stem cell model, based on the properties of cancer stem cells, derived from transgenic MMTV-PyMT mice. Using a defined set of cell surface markers to identify cancer stem cells by flow cytometry, at least four cell populations were recovered from primary mammary cancers. Only two of the four populations, one epithelial and one mesenchymal, were able to survive and proliferate in vitro. The epithelial population exhibited tumor initiation potential with as few as 10 cells injected into syngeneic immune-competent recipients. Tumors initiated from injected cell lines recapitulated the morphological and physiological components of the primary tumor. To highlight the stemness potential of the putative cancer stem cells, B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) expression was knocked down via shRNA targeting Bmi-1. Without Bmi-1 expression, putative cancer stem cells could no longer initiate tumors, but tumor initiation was rescued with the introduction of a Bmi-1 overexpression vector in the Bmi-1 knockdown cells. In conclusion, our data show that primary mammary cancers from MMTV-PyMT mice contain putative cancer stem cells that survive in culture and can be used to create a model for study of mammary cancer stem cells.
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http://dx.doi.org/10.1007/s13277-012-0458-4DOI Listing
December 2012

Tumor-derived mesenchymal stem cells and orthotopic site increase the tumor initiation potential of putative mouse mammary cancer stem cells derived from MMTV-PyMT mice.

Tumour Biol 2012 Dec 27;33(6):1997-2005. Epub 2012 Jul 27.

Translational and Functional Genomics Laboratory, Ordway Research Institute, Albany, NY 12208, USA.

The ability to transplant mammary cancer stem cells, identified by the phenotype CD24(+)CD29(+)CD49f(+)Sca-1(low), is dependent on the microenvironment in which the cells are placed. Using the MMTV-PyMT mouse model of mammary cancer, we now report two methods of tumor growth enhancement: contributions of tumor stroma in the form of tumor-derived mesenchymal stem cells and orthotopic vs. heterotopic transplantation sites. To support evidence of stem cell function, tumor-derived mesenchymal stem cells differentiated into adipocyte- and osteocyte-like cells after culture in specific medium. Co-injection of tumor-initiating cells with tumor-derived mesenchymal stem cells significantly increased tumor initiation compared to subcutaneous injection of TICs alone; co-injection also allowed tumor initiation with a single TIC. Interestingly, we observed the formation of sarcomas after co-injections of tumor-derived mesenchymal stem cells or mouse embryonic fibroblasts with TICs; sarcomas are not observed in spontaneous MMTV-PyMT tumors and rarely observed in injections of TICs alone. Tumor initiation was also significantly increased in the orthotopic injection site compared to heterotopic injections. We conclude that tumor stroma and orthotopic sites both enhance tumor initiation by mammary cancer stem cells.
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http://dx.doi.org/10.1007/s13277-012-0459-3DOI Listing
December 2012

Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders.

Cell Cycle 2011 Oct;10(20):3571-97

Translational and Functional Genomics Laboratory, Genlighttechnology Corporation, La Jolla, CA, USA.

The mechanistic relevance of intergenic disease-associated genetic loci (IDAGL) containing highly statistically significant disease-linked SNPs remains unknown. Here, we present experimental and clinical evidence supporting the importantance of the role of IDAGL in human diseases. A targeted RT-PCR screen coupled with sequencing of purified PCR products detects widespread transcription at multiple IDAGL and identifies 96 small noncoding trans-regulatory RNAs of ~100-300 nt in length containing SNPs (snpRNAs) associated with 21 common disorders. Multiple independent lines of experimental evidence support functionality of snpRNAs by documenting their cell type-specific expression and evolutionary conservation of sequences, genomic coordinates and biological effects. Chromatin state signatures, expression profiling experiments and luciferase reporter assays demonstrate that many IDAGL are Polycomb-regulated long-range enhancers. Expression of snpRNAs in human and mouse cells markedly affects cellular behavior and induces allele-specific clinically relevant phenotypic changes: NLRP1-locus snpRNAs rs2670660 exert regulatory effects on monocyte/macrophage transdifferentiation, induce prostate cancer (PC) susceptibility snpRNAs and transform low-malignancy hormone-dependent human PC cells into highly malignant androgen-independent PC. Q-PCR analysis and luciferase reporter assays demonstrate that snpRNA sequences represent allele-specific "decoy" targets of microRNAs that function as SNP allele-specific modifiers of microRNA expression and activity. We demonstrate that trans-acting RNA molecules facilitating resistance to androgen depletion (RAD) in vitro and castration-resistant phenotype (CRP) in vivo of PC contain intergenic 8q24-locus SNP variants (rs1447295; rs16901979; rs6983267) that were recently linked with increased risk of PC. Q-PCR analysis of clinical samples reveals markedly increased and highly concordant (r = 0.896; p < 0.0001) snpRNA expression levels in tumor tissues compared with the adjacent normal prostate [122-fold and 45-fold in Gleason 7 tumors (p = 0.03); 370-fold and 127-fold in Gleason 8 tumors (p = 0.0001) for NLRP1-locus and 8q24-locus snpRNAs, respectively]. Our experiments indicate that RAD and CR phenotype of human PC cells can be triggered by ncRNA molecules transcribed from the NLRP1-locus intergenic enhancer at 17p13 and by downstream activation of the 8q24-locus snpRNAs. Our results define the IDAGL at 17p13 and 8q24 as candidate regulatory loci of RAD and CR phenotypes of PC, reveal previously unknown molecular links between the innate immunity/inflammasome system and development of hormone-independent PC and identify novel molecular and genetic targets with diagnostic and therapeutic potentials, exploration of which should be highly beneficial for personalized clinical management of PC.
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http://dx.doi.org/10.4161/cc.10.20.17842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266183PMC
October 2011

Inflammatory chemokine receptors regulate CD8(+) T cell contraction and memory generation following infection.

J Exp Med 2011 Aug 25;208(8):1621-34. Epub 2011 Jul 25.

Trudeau Institute, Saranac Lake, NY 12983, USA.

The development of T cell memory from naive precursors is influenced by molecular cues received during T cell activation and differentiation. In this study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8(+) T cell contraction and memory generation after influenza virus infection. We find that Ccr5(-/-) Cxcr3(-/-) cells show markedly decreased contraction after viral clearance, leading to the establishment of massive numbers of memory CD8(+) T cells. Ccr5(-/-) Cxcr3(-/-) cells show reduced expression of CD69 in the lung during the peak of infection, which coincides with differential localization and the rapid appearance of memory precursor cells. Analysis of single chemokine receptor-deficient cells revealed that CXCR3 is primarily responsible for this phenotype, although there is also a role for CCR5 in the enhancement of T cell memory. The phenotype could be reversed by adding exogenous antigen, resulting in the activation and contraction of Ccr5(-/-) Cxcr3(-/-) cells. Similar results were observed during chronic Mycobacterium tuberculosis infection. Together, the data support a model of memory CD8(+) T cell generation in which the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8(+) T cell activation and differentiation, which ultimately regulates effector versus memory cell fate decisions.
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http://dx.doi.org/10.1084/jem.20102110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149221PMC
August 2011

The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity.

Am J Dermatopathol 2011 Jul;33(5):433-60

Divisions of Dermatopathology and Dermatology, Department of Pathology, Albany Medical College, Albany, NY, USA.

Syphilis has plagued mankind for centuries and is currently resurgent in the Western hemisphere. Although there has been a significant reduction of tertiary disease and recognition of facilitative interactions with human immunodeficiency virus infection, the natural history of syphilis has remained largely unchanged; thus, new strategies are required to more effectively combat this pathogen. The immunopathologic features of experimental syphilis in the rabbit; the course, stages, and pathology of human syphilis; and a comparison of human syphilis with leprosy suggest that the clinical course of syphilis and its tissue manifestations are determined by the balance between delayed-type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease. Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and, more importantly, activation of macrophages by sensitized CD4 T cells. The Bacillus Calmette-Guerin vaccination can enhance DTH and has been shown to produce a low, but measurable, beneficial effect in the prevention of leprosy, a disease that shows a disease spectrum with characteristics in common with syphilis. In the prevention of syphilis, a potential vaccine protective against syphilis should be designed to augment the DTH response.
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http://dx.doi.org/10.1097/DAD.0b013e3181e8b587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690623PMC
July 2011