Our laboratories have recently developed a two element method for the induction of tolerance to murine islet allografts. The combination of small donor lymphocytes and an antibody directed against the co-activation molecule CD40 ligand (CD40L) has enabled us to achieve permanent islet allograft survival. This Project is intended to extend our initial observations to islet xenograft systems. We have published data showing that our two element protocol can substantially prolong the survival of both rat islet and skin xenografts in mice. In this proposal, we will 1) identify the optimal parameters for tolerance induction in normal mice engrafted with islets and skin of both rat and human origin and 2) identify the host immune response elements that permit xenograft survival in tolerized mice (Specific Aim #1). These model systems will then be investigated further in adoptive transfer studies using scid mouse recipients to identify the cellular mechanisms that permit xenograft survival in tolerized mice (Specific Aim #2). The mechanisms identified will be compared with those mechanisms found to be responsible for allograft tolerance in Project 1. This is an important objective because neither the identity nor the functional capabilities of the cellular elements which participate in xenograft vs. allograft rejection are known with certainty. Our third objective is to extend our two element tolerance induction protocol to the human immune system. We have developed a method for creating complete xenogeneic lymphohemopoietic chimeras using the NOD-scid mouse engrafted with human peripheral blood lymphocytes (Hu-PBL-NOD-scid mice). Hu-PBL-NOD-scid mice will be used to induce, tolerance in the engrafted human immune system to xenogeneic islets and skin (Specific Aim #3). Although directed primarily at the study of islet xenografts, the chimera technology developed for this Aim will also permit us 1) to study the induction of tolerance to human islet allografts in a small animal model system, and 2) to compare in this system PBLs from normal individuals with those obtained from patients with insulin-dependent diabetes mellitus (IDDM). Our overall goal is to induce xenotolerance in the human immune system using a two element method that can be adapted to clinical practice. We believe it realistic to hope that this method may eventually prove suitable for curing diabetes mellitus.

Project Start
2000-12-01
Project End
2001-11-30
Budget Start
Budget End
Support Year
4
Fiscal Year
2001
Total Cost
$180,000
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Covassin, L; Laning, J; Abdi, R et al. (2011) Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2r?(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol 166:269-80
de Vries, V C; Elgueta, R; Lee, D M et al. (2010) Mast cell protease 6 is required for allograft tolerance. Transplant Proc 42:2759-62
Brehm, Michael A; Bortell, Rita; Diiorio, Philip et al. (2010) Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice. Diabetes 59:2265-70
Jurczyk, Agata; Pino, Steven C; O'Sullivan-Murphy, Bryan et al. (2010) A novel role for the centrosomal protein, pericentrin, in regulation of insulin secretory vesicle docking in mouse pancreatic beta-cells. PLoS One 5:e11812
Brehm, Michael A; Shultz, Leonard D; Greiner, Dale L (2010) Humanized mouse models to study human diseases. Curr Opin Endocrinol Diabetes Obes 17:120-5
Racki, Waldemar J; Covassin, Laurence; Brehm, Michael et al. (2010) NOD-scid IL2rgamma(null) mouse model of human skin transplantation and allograft rejection. Transplantation 89:527-36
Brehm, Michael A; Cuthbert, Amy; Yang, Chaoxing et al. (2010) Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol 135:84-98
Mangada, Julie; Pearson, Todd; Brehm, Michael A et al. (2009) Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice. Diabetes 58:165-73
King, M A; Covassin, L; Brehm, M A et al. (2009) Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol 157:104-18
Pearson, T; Shultz, L D; Lief, J et al. (2008) A new immunodeficient hyperglycaemic mouse model based on the Ins2Akita mutation for analyses of human islet and beta stem and progenitor cell function. Diabetologia 51:1449-56

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