The objective of this proposal is to develop a novel ECP-based donor cell therapy for the induction of donor-specific tolerance in the setting of living donor organ transplantation. Our preliminary data support that pre-transplant infusion of ECP treated donor cells promote tolerance induction and may reduce or eliminate the need for long term use of immunosuppressive medications, which would significantly reduce associated morbidities and mortalities in these patients. We have tested ECP in several murine and rat models, utilizing fully MHC-mismatched strains of immunocompetent animals, and shown that a single infusion of ECP-treated donor-type leukocytes (ECP-DLs) seven days prior to solid organ transplant significantly improves heart, liver and kidney allograft survival. We have demonstrated a synergistic effect of common IS drugs along with the ECP treatment pre-transplant donor cells, and in the liver model, the addition of post-transplant ECP treatment of recipient peripheral blood leukocytes further improved the gross and histologic appearance of the transplanted liver; liver function testing was also superior in this group. Across the three models, we have proven this is a donor specific process, and have seen a decrease in inflammatory infiltrate in the transplanted organs, inhibition of T-cell priming and response, and donor specific antibody production. Finally, we have found an increase in T-regulatory cell production in those animals treated with ECP-DLs. However, little is known about the safety and efficacy of ECP treated donor cells in prevention of allograft rejection. Prior to initiation of clinical trials utilizing our novel approach of infusing ECP-treated donor cells prior to solid organ transplant in a living donor-recipient pair, small animal models may be utilized to test its efficacy, and to provide a deeper understanding of its mechanism of action on human cells in this capacity. Preclinical testing of therapeutic immune modulations has been limited in murine models due to species difference in biologic responses. To overcome these constraints, several humanized mouse models have been developed by reconstitution of human PBMCs or stem cells in immune deficient mice. We propose to use NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice (20-30 g), also known as NSG mice. NSG mice combine the features of the NOD/ShiLtJ background, the severe combined immune deficiency mutation (scid) and IL2 receptor gamma chain deficiency. As a result, these NSG mice lack mature T cells, B cells, and functional NK cells; they are also deficient in cytokine signaling, leading to better engraftment of human hematopoietic stem cells and peripheral-blood mononuclear cells than any other published mouse strain. Therefore, this model is extremely valuable to investigate the ability of human immunotherapies to enhance or suppress functional human immune responses. Recent publications have demonstrated this strain's outstanding utility in the studies of transplantation and stem cell differentiation serving. We and others have shown that un-manipulated NSG mice can readily accept a piece of human skin transplanted on it, while humanized NSG mice reliably and predictably reject donor skin grafts by HLA mismatched human PBMCs (“recipient” via a human T-cell mediated mechanism. In addition, humanized mouse models of xenogeneic- graft–versus-host response/disease (GVHD) based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; “Hu-PBMC mice”) are important tools to study human immune function . Specific Aim
|Effective start/end date||6/1/17 → 11/30/18|
- Ann & Robert H. Lurie Children’s Hospital of Chicago (939021-NU)
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