This is Project 3 of the consortium proposal focused on the manipulation of hematopoietic and mesenchymal stem cells for the control of donor-specific alloreactivity in Cynomolgus monkeys. This project will define the role of regulatory T cells and cytokines in allograft acceptance of allogeneic islet and kidney transplantation. A central role of T immune regulatory cells in the maintenance of transplant tolerance is an emerging concept requiring critical evaluation in non-human primate models of allograft transplantation. Early studies with murine transplantation models had suggested that suppression of Thl cytokine responses, primarily IFN-gamma, and enhancement of Th2 responses, primarily IL-4, were critical for tolerance. These observations were consistent with the prevailing concepts that IL-4 could negatively regulate Thl cytokine responses and that IFN-gamma was proinflammatory. More recently the cytokines IL-l0 and TGF-beta, which have anti-inflammatory properties, have been implicated in the maintenance of tolerance. Specifically, a subset of CD4+ T cells, designated T regulatory cells, has been demonstrated to inhibit antigen-specific immune responses through the secretion of IL-l0 and TGF-beta and expression of CTLA-4. T regulatory cells have been identified in models of autoimmunity and allograft tolerance in mice and humans. This has led to a compelling new hypothesis of allograft tolerance in which T regulatory cells, producing IL-l0 and/or TGFbeta, are the primary mediators of peripheral allograft tolerance. Under this hypothesis, the tolerant state is a dynamic one in which proinflammatory cells are held in check by T regulatory cells. Our murine model of tolerance involving co transplantation of intact active bone fragments (JAB) and transient costimulation blockade results in stable, long-term tolerance. Investigations into the mechanism maintaining the tolerant state suggest a role for IL-l0-producing T regulatory cells. Preliminary results in a Cynomolgus monkey that accepted an allogeneic kidney graft for more than 145 days are also consistent with a hypothesis that, in immunologically intact recipients, a dominance of T regulatory cells over proinflammatory T cells produces long-term allograft acceptance. Here we propose to test whether allograft tolerance induced by non-myeloablative regimens in the setting of allogeneic islet and renal transplantation in non-human primates depends on a dominant T regulatory cell population. We also propose to test whether bone marrow- derived mesenchymal stem cells can enhance the development of T regulatory cells. We anticipate that these mechanistic studies will lead to an increased understanding of the roles of cytokines and T regulatory cells in allograft acceptance and tolerance. Our proposed studies will also evaluate ex vivo cytokine assays as biomarkers of immune tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI051728-01
Application #
6660584
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2002-09-15
Project End
2007-06-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Addicott, Benjamin; Willman, Melissa; Rodriguez, Jose et al. (2011) Mesenchymal stem cell labeling and in vitro MR characterization at 1.5 T of new SPIO contrast agent: Molday ION Rhodamine-B™. Contrast Media Mol Imaging 6:7-18
Berman, Dora M; Willman, Melissa A; Han, Dongmei et al. (2010) Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes 59:2558-68
Han, Dongmei; Berman, Dora M; Willman, Melissa et al. (2010) Choice of immunosuppression influences cytomegalovirus DNAemia in cynomolgus monkey (Macaca fascicularis) islet allograft recipients. Cell Transplant 19:1547-61
Bartholomew, Amelia; Polchert, David; Szilagyi, Erzsebet et al. (2009) Mesenchymal stem cells in the induction of transplantation tolerance. Transplantation 87:S55-7
Alegre, Maria-Luisa; Goldstein, Daniel R; Chong, Anita S (2008) Toll-like receptor signaling in transplantation. Curr Opin Organ Transplant 13:358-65
Lee, D D; Grossman, E; Chong, A S (2008) Cellular therapies for type 1 diabetes. Horm Metab Res 40:147-54
Wang, Tongmin; Chen, Luqiu; Ahmed, Emily et al. (2008) Prevention of allograft tolerance by bacterial infection with Listeria monocytogenes. J Immunol 180:5991-9
Li, Yijin; Ma, Lianli; Yin, Dengping et al. (2008) Long-term control of alloreactive B cell responses by the suppression of T cell help. J Immunol 180:6077-84
Xiang, Zhidan; Ma, Lian-Li; Manicassamy, Santhakumar et al. (2008) CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation 85:1205-11
Ma, Lianli; Xiang, Zhidan; Sherrill, Taylor P et al. (2008) Bioluminescence imaging visualizes activation of nuclear factor-kappaB in mouse cardiac transplantation. Transplantation 85:903-10

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