Stanislaw Stepkowski, D.V.M., Ph.D., D.Sc.
Professor
Department of Medical Microbiology and Immunology
Joint Appointment, Department of Surgery
Office: HEB 237
Phone: 419.383.6626
Fax: 419.383.3002
E-mail Address: Stanislaw.Stepkowski@utoledo.edu
Dr. Stepkowski was educated in Warsaw, Poland (Veterinary Medicine/Polish Academy
of Sciences), trained at Radium Hospital in Oslo, Norway (PhD), Dalhousie University
in Halifax, Canada (postdoctoral), and at the University of Texas in Houston, USA
(DSc). For the last ten years, he has worked at The University of Toledo College of
Medicine. Although he was very privileged to work in different countries, he considers
the United States as his home and the best place to perform the most advanced research. Chronic allograft rejection project:His most recent interest is on discovery of better methods to prevent chronic graft
injury by better understanding hypertension-induced nephropathy. While advances in
immunosuppression have greatly improved the survival of heart transplants, their long-term
survival is hindered by the process of cardiac allograft vasculopathy (CAV). This
slowly progressing occlusion of the coronary arteries begins shortly after heart transplantation.
Pathologically, CAV is a concentric intimal smooth muscle hyperplasia along the vessel,
which gradually obstructs its lumen. The process is complicated by local inflammatory
infiltrates by macrophages and lymphocytes. In drastic cases, transplants develop
CAV quickly producing graft failure within 2 years post-transplant. The development
of CAV is responsible for almost 30% of deaths at 5-years after heart transplantation. Kidney paired donation project:For the last 10 years, Stepkowski's lab is involved in a clinical program called kidney paired donation (KPD). The KPD program facilitates exchanges of donors among patients with live incompatible donors. Recent analysis examined what happened during a 6-year period to 1,121 end-stage renal disease patients who registered with their incompatible living donors for kidney exchanges with the Alliance for Paired Donation (APD). Of all patients, 65% were transplanted: 37% in kidney paired donation (APD-KPD, APD-other-KPD); 10% with compatible live donors (APD-LD); and 18% with deceased donors (APD-DD). The remaining patients were withdrawn (sick/died/others; 15%), or were still waiting (20%). For patients with a cPRA 0-94%, as many as 72% received a transplant. In contrast, only 49% of very highly sensitized (VHS; cPRA 95-100%) were transplanted. Of the VHS patients, 50% were transplanted by KPD/APD-LD while 50% benefited through prioritization of deceased donors in the modified kidney allocation system (KAS) introduced in 2014. All APD transplanted groups had similar death-censored 4-year graft survivals as their relevant OPTN groups. It is noteworthy that VHS graft and patient survival results were comparable to less sensitized and non-sensitized patients. All patients should be encouraged to search for compatible donors through different options. Expanding the donor pool through KPD and the new KAS of the OPTN increases the likelihood of transplantation for VHS patients. New method for producing long-term kidney allograft survival:The newest clinical interest by Stepkowski's lab is focused on the role of human leukocyte
antigen (HLA) in kidney allograft rejection. The impact of the human leukocyte antigen
(HLA)-A/B/DR mismatch (MM) on kidney allograft survival has been a subject of extensive
research. While some researchers argued that the role of HLA matching is exaggerated,
the consensus is that HLA compatibility is vital for long-term kidney and other organs
outcomes. Indeed, fully matched transplants at HLA-A/B/DR called 0-HLA mismatch consistently
demonstrate the best kidney allograft survivals whereas the worse 6-HLA mismatch have
the worst outcomes. The remaining 1-, 2-, 3-, 4-, and 5-HLA mismatch groups demonstrated
incrementally distributed survivals between 0- and 6-HLA MM cohorts. Decreasing overall
HLA immunogenicity (IM) of prospective kidney transplants would proffer significant
benefits, such as extended median graft survival. Currently, an average survival for
kidney allografts is 10 years for deceased donors and 12 years for live donors. Development of new immunosuppressive modalities:Dr. Stepkowski's interests are in cellular and organ transplantation, with research
focused on improvement of long-term allograft survival and development of new immunosuppressive
modalities. Activation of T lymphocytes requires three overlapping and sequential
signals, with signal 3 delivered by multiple cytokines that regulate cell proliferation,
differentiation, and survival/death. Cytokines binding to their receptors engages
two key molecular families, namely, Janus tyrosine kinases (Jaks) and signal transducers
and activators of transcription (Stats). Among Jaks, gamma-cytokines bind to cytokine
receptors consisting gamma-chain, thereby engaging Jak3/Stat5 cascade leading to proliferation
and differentiation of T cells. Recently, novel tyrosine (Y905 and Y935) phosphorylation
sites are investigating on Jak3 and their role in T cell function. Mice with mutated
these tyrosines are being produced to examine in vivo impact on development and function
in T cells. Similarly, Stat3 and Stat5 are investigated for their role in regulating
T cells. Binding of cytokines to cytokine receptors attracts and activates one or
more of the Jaks, which are tyrosine phosphorylated themselves and phosphorylate tyrosines
on the cytokine receptor sites thereby creating active docking sites for Stats. Among
Stats, recent evidence suggests that Stat3 is involved in the generation of a new
population of T helper 17 (Th17) cells, and in the regulation of dendritic cell function
and the process of angiogenesis. We are investigating whether Stat3 deficiency may
affect the regulation of Th17 cells and other functions. Based on screening of multiple
compounds from NIH data base, novel and selective inhibitor of Jak3, NC1153, has been
developed. It has been shown that NC1153 may inhibit kidney allograft rejection in
rats and cynomolgus monkeys. Most of this work has been published in the Journal of
Immunology, Blood, and Transplantation. grant funding over the last ten years:NSF/NIH (RFA/PA # PAR-19-004 Program); Co-PI, Stanislaw Stepkowski; Title: "Machine
learning and network science for predicting kidney transplant survival": Direct award
$200,000 per year, 07/01/2019-6/31/2023. The total award: $750,000. This collaborative
grant proposal with Dr. Kevin Xu (UT, College of Mechanical Engineering) is designed
to apply a machine-learning technology to improve the selection of donors for patients
waiting for a kidney transplant. Donor and recipient HLA antigens are evaluated for
better HLA matching to improve long-term kidney allograft survivals. peer reviewed representative publications out of 217 papers:Khattar M, Baum C, Schroder P, Breidenbach J, Haller S, Chen W, Stepkowski S. IL-21 regulates chronic allograft vasculopathy (CAV) in murine heart allograft rejection. PloS One 14:e0225624, 2019Stepkowski S, Mierzejewska B, Fumo D, Bekbolsynov D, Khuder S, Baum CE, Brunner RJ, Kopke JE, Rees SE, Smith CE, Ashlagi I, Roth AE, Rees MA. The 6-year outcomes for patients registered in a multiregional United States Kidney Paired Donation program. Transplant International 32:839-853, 2019 Stepkowski S. Histocompatibility leukocyte antigen and organ transplantation: love and hate relationship. Curr. Opin. Organ Transpl. 23:467, 2018 Dolin HH, Papadimos Stepkowski S, TJ, Chen X, Pan ZK. A novel combination to herald the onset of sepsis prior to the manifestation of symptoms. Shock 49:364, 2018 Haller S, Kumarasamy S, Stepkowski S, Folt D, Wuescher L, Bina J, Shapiro J, Cooper C. Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure, in hypertensive nephropathy. Kidney International, 91:365-74, 2017 Fumo DE, Kapoor V, Reece LJ, Stepkowski SM, Kopke JE, Rees SE, Smith C, Roth AE, Leichtman AB, Rees MA. Historical matching strategies in kidney paired donation: the 7-year evolution of a web-based virtual matching system. American J. Transpl. 15:2646-54, 2015 [PMID:26015291 Schroder P, Khattar M, Baum CE, Miyahara Y, Vyas R, Muralidharan S, Mierzejewska B, Stepkowski SM. PD-1-dependent restoration of self-tolerance in diabetic NOD mice after transient anti-TCRb mAb restoration of self-tolerance in diabetic NOD mice after transient anti-TCRb mAb therapy. Diabetologia 58:1309-18, 2015 [PMID:2594782 Xie A, Zheng X, Khattar M, Schroder P, Xia J, Stepkowski S, Chen W. TCR stimulation without co-stimulatory signals induces expression of tolerogenic genes in memory CD4 T cells but does not compromise cell proliferation. Molecular Immunology 63:406-11, 2014 [co-senior author] [PMID:25306961] Mierzejewska B, Schroder PA, Baum C, Rees M, Stepkowski SM. Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP. Human Immunology 75:703-8, 2014 [S0198-8859 Deng R, Xie A, Schroder PM, Khattar M, Chen W, Stepkowski SM. Anti-TCR mAb induces perioheral tolerance to alloantigens and depays islet allograft rejection in autoimmune diabetic NOD mice. Transplantation 97:1216-24, 2014 Mierzejewska B, Baum C, Schroder PA, Durlik M, Lisik W, Rees M, Stepkowski SM. Diversity in kidney paired donation programs accommodates local requirements. Annals of Transplantation 18:112-24, 2013 Khattar M, Deng R, Kahan BD, Schroder PM, Phan T, Rutzky LP, Stepkowski SM. Novel sphingosin-1-phosphate receptor modulator KRP203 combined with locally-delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts. Transplantation 95:919-27, 2013 Guo Z,Khattar M, Schroder PM, Miyahara Y, Wang G,He X, Chen W, Stepkowski SM. A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells. Journal of Immunology 190:3153-62, 2013 Miyahara Y, Khattar M, Schroder P, Mierzejewska B, Deng R, Han R, Hancock WW, Chen W, Stepkowski SM. An anti-TCR monoclonal antibody induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells. American J Transplantation 12:1409-18, 2012 Li J, Chen G, Ye P, Wang S, Zhang K, Chen W‡, Stepkowski SM, Junhua Li J, Zhong S, Xia J. CCR5 Blockade in Combination with Cyclosporine Increased Cardiac Graft Survival and Generated Alternatively Activated Macrophages in Primates. J. Immunol. 186:3753-61, 2011. Wang G, Guo Z, Miyahara Y, Khattar M, Linkes SP, Sun Z, He X, Stepkowski SM, Chen W. "Default" generation of neonatal regulatory T Cells. J. Immunol. 185:71, 2010. Guo Z, Wang G, Miyahara Y, Khattar M, Linkes SP, Wang C, Xia J, Pan Y, Chen W, He X, Stepkowski SM. IL-7, but not thymic stromal lymphopoietin (TSLP), contributes to the programmatic generation of memory CD4+ T cells. Immunol Lett. 128:116, 2010. Wang G, Khattar M, Guo Z, Miyahara Y, Linkes SP, Sun Z, He X, Stepkowski SM, Chen W. IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms of CD4+CD25+ regulatory T cell which jointly restrain CD4+CD25- cell activation. Immunol Lett. 132:61, 2010. Fernandes I, Zhang Y, Qi Y, Wang ME, Podder H, Lisik W, Knight R, Kahan BD, Stepkowski SM. Impact of reduced nephron mass on cyclosporine- and/or sirolimus-induced nephrotoxicity. Transplantation. 88:1323, 2009. Khattar M, Chen W, Stepkowski SM. Expanding and converting regulatory T cells. Arch. Immunol. Ther. Exp. 57:199, 2009. Wang G, Khattar M, Guo Z, Miyahara Y, Linkes SP, Sun Z, He X, Stepkowski SM, Chen W. IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms Wang G, Khattar M, Guo Z, Miyahara Y, Linkes SP, Sun Z, He X, Stepkowski SM, Chen W. IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms of CD4(+)CD25(+) regulatory T cell which jointly restrain CD4(+)CD25(-) cell activation. Immunol Lett. 2010 June 8. [Epub ahead of print]. Guo G, Wang G, Miyahara Y, Khattar M, Linkes SP, Want C, Xia J, Pan Y, Chen W, He X, Stepkowski SM. IL-7, but not thymic stromal lymphopoietin (TSLP), contributes to the programmatic generation of memory CD4+ T cells. Immunol. Lett. 2010 128:116-123. Wang G, Miyahara Y, Guo Z, Khattar M, Stepkowski SM, Chen W. (2010) Default generation of neonatal regulatory T cells. J Immunol. 185:71-78 . Khattar M, Chen W, Stepkowski SM (2009) Expanding and converting regulatory T cells: a horizon for immunotherapy. Arch Immunol Ther Exp (Warsz).57(3): 199-204. Chen W, Diao J, Stepkowski SM, Zhang L. Both infiltrating regulatory T cells and insufficient antigen presentation are involved in long-term cardiac xenograft survival. J Immunology 179(3):1542-8, 2007. Razeghi P, Wang ME, Youker KA, Golfman L, Stepkowski S, Taegtmeyer H. Lack of NF-kappaB1 (p105/p150) attenuates unloading-induced downregulation of PPARalpha and PPARalpha-regulated gene expression in rodent heart. Cardiovasc Res 74:133, 2007. Razeghi P, Volpini KC, Wang ME, Youker KA, Stepkowski S, Polonsky KS, Taegtmeyer H. Mechanical unloading of the heart activates the calpain system. J Mol & Cellular Cardiol 42:449, 2007. Stepkowski SM, Phan T, Zhang H, Bilinski Sz, Kloc M, Yuhua Qi Y, Katz SM, Rutzky LP. Immature syngeneic dendritic cells (DC) potentiate tolerance to islet allografts depleted of passenger DC by culturing in bioreactors. Transplantation 82:1756, 2006. Nagy ZS, Rui H, Stepkowski SM, Karras J, Kirken RA. A preferential role for STAT5, not constitutively active STAT3, in promoting survival of human lymphoid tumor. J Immunol 177:5032-5040, 2006. Razeghi P, Buksinska-Lisik M, Palanichamy N, Stepkowski SM, Frazier OH, Taegtmeyer H. Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart. FASEB Journal, 20:1090-6, 2006. Razeghi P, Baskin KK, Sharma S, Young ME, Stepkowski SM, Fssop F, Teagtmayer H. Atrophy, hypertrophy and hypoxemia induce transcriptional regulators of the ubiquitin proteosome system in the rat heart. Biochem Biophys Res Commun, 342:361-4, 2006. Stepkowski SM, Kirken RA. Janus tyrosine kinase and signal transducers and activators of transcription regulate critical functions of T cells in allograft rejection and transplantation tolerance. Transplantation 82:295-303, 2006. Sharma S, Ying J, Razeghi P, Stepkowski SM, Taegtmeyer H. Atrophic remodeling of the transplanted rat heart. Cardiology 105:128-136, 2006. Stepkowski SM, Kirken R. Unique advantage of Janus tyrosine kinase for selective and non-toxic immunosuppression. Exp Rev Clin Immunol in press 2005. Zhang Y, Kirken RA, Furian L, Janczewska S, Qu X, Hancock WW, Wang ME, Tejpal N, Kerman R, Kahan R, Stepkowski SM. Allograft rejection requires Stat5a/b-regulated anti-apoptotic activity in T but not in B cells. Journal of Immunology 176:128-137, 2006. Stepkowski SM, Kao J, Wang ME, Tejpa N, Podder H, Furian L, Dimmock J, Jha A§, Das U, Kahan BD, Kirken RA. The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities. J Immunol 175:4236, 2005. Hong M, Hong C J, Fernandes I, Stepkowski SM, Kahan BD. Correlation between cyclosporine-induced nephrotoxicity and reduced-nephron mass and the expression of kidney injury molecule-1 and aquaporin-2 genes. Transpl Proc in press 2005. Chen W, Langer RM, Janczewska S, Furian L, Geary R, Qu X, Wang M-E, Verani R, Condon T, Stecker K, C Frank Bennett CF, Stepkowski SM. Methoxyethyl-modified ICAM-1 antisense phosphorotioateoligonucleotides inhibit allograft rejection, ischemic/reperfusion injury, and cyclosporine-induced nephrotoxicity. Transplantation 79:401-8, 2005. Kahan BD, Stepkowski SM, Kilic M, Katz SM, Van Buren CT, Welsh MS, Tami JA, Shanahan WR Jr. Phase I and II safety and efficacy trial of intercellular adhesion molecule-1 antisense oligonucleotides (ISIS 2302) for prevention of acute allograft rejection. Transplantation 78:858-63, 2004. Langer R, Wang M, Stepkowski SM, Hancock WW, Han R, Li P, Lili Feng5, Kirken RA, Kurt L. Berens, KL, Dupre B, Podder H, Dixon RAF, Kahan BD. Selection inhibitor Bisosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines. J American Soc Neph 15:2893, 2004. Nagy ZS, Ross J, Cheng H, Stepkowski SM, Kirken RA. Regulation of lymphoid cell apoptosis by Jaks and Stats. Critcal Rev Immunol 24:87-110, 2004. Bai S, Stepkowski SM, Kahan BD, Brunner LJ. Metabolic interaction between cyclosporine and sirolimus. Transplantation 77:1507-12, 2004. Razeghi P, Sharma S, Ying J, Li Y-P, Stepkowski SM, Reid M, Teagtmeyer H. Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation. Circulation 108:2536-41, 2003. Behbod F, Stepkowski SM, Karras J, Johnson CR, Jarvis WD, Kirken RA. Specific inhibition of signal transducer and activator of transcription 5a and 5b (Stat5a/b) promotes apoptosis of IL2-responsive primary and tumor-derived lymphoid cells. J Immunol 117:3919-3927, 2003. Doenst T, Goodwin GW, Cedars AM, Wang M, Stepkowski S, Taegtmeyer H. Load-induced changes in vivo alter substrate fluxes and insulin responsivness of rat heart in vitro. Metabolism 50:1083-90, 2001. Perez J, Stepkowski SM, Trawick B, Wang M-E, Janczewska S, Kahan BD. Selection of low immunogenic and highly tolerogenic donor/recipient allochimeric class I MHC proteins. Transplantation 76:1201-7, 2003. Janczewska S, Wisniwski M, Stepkowski SM, Lukomska B. Fast hematopoietic recovery after bone marrow engraftment needs physiological proximity of stromal and stem cells. Cell Transplantation, 12:399-406, 2003. |