Abstract

This proposal focuses upon understanding the functions of antigen activated populations of host leukocytes, their products and their interrelationships which are mobilized in response to a vascularized organ allograft; these responses include both the events of acute rejection of cardiac grafts in untreated histoincompatible rat recipients and those responsible for prolonged survival in immunologically modified hosts. The role of activated leukocytes developing receptors for interleukin 2 (IL2R+ cells) in rejection will be emphasized, and their modulation by various IL2R targeted therapies assessed, a novel approach to specific immunosuppression. In particular, these therapies will be used as probes to determine function and kinetics of IL2R+ cells infiltrating the graft and occurring in host peripheral lymphoid tissues, the influence of these cells on other populations and their effect on cytokine production. For comparison, IL2R+ cells will be investigated in other states of host unresponsiveness, including animals treated with cyclosporine (CsA), or in immunological enhancement. The differential functions, interactions and migrational properties of T helper (Th,CD4) and T cytotoxic/suppressor (Tc/s,CD8) phenotypes will be defined serially; specifically, the putative sparing effect of IL2R directed therapies on cells with suppressor activity will be examined. Isolated IL2R+ macrophages, an important component of the IL2R+ infiltrate, will be cultured then stimulated with cytokines or down regulated with CsA. Function of these regulated cells will then be assessed in vivo by transfer studies. Dendritic cells will be studied as inducers of immune responsiveness in the context of transplantation, with emphasis on their role in activating resting T lymphocytes to develop IL2R, as well as their migration patterns. The differential production and function of cytokines will be investigated in anti-IL2R treated recipients, stressing their effects on lymphocyte subpopulations in vivo. Taken together, these studies should delineate the role of antigen activated IL2R+ leukocytes in host responsiveness toward vascularized organ allografts. Their modulation by specific therapies may be critical in clinical transplantation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046190-21
Application #
2145375
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1982-08-01
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
21
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Harvard University
Department
Surgery
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Gasser, Martin; Waaga-Gasser, Ana Maria; Grimm, Michael W et al. (2005) Selectin blockade plus therapy with low-dose sirolimus and cyclosporin a prevent brain death-induced renal allograft dysfunction. Am J Transplant 5:662-70
Pratschke, Johann; Paz, Dustin; Wilhelm, Markus J et al. (2004) Donor hypertension increases graft immunogenicity and intensifies chronic changes in long-surviving renal allografts. Transplantation 77:43-8
Gasser, Martin; Waaga, Ana Maria; Kist-Van Holthe, Joana E et al. (2002) Normalization of brain death-induced injury to rat renal allografts by recombinant soluble P-selectin glycoprotein ligand. J Am Soc Nephrol 13:1937-45
Laskowski, Igor A; Pratschke, Johann; Wilhelm, Markus J et al. (2002) Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats. J Am Soc Nephrol 13:519-27
Wilhelm, M J; Pratschke, J; Beato, F et al. (2002) Activation of proinflammatory mediators in heart transplants from brain-dead donors: evidence from a model of chronic rat cardiac allograft rejection. Transplant Proc 34:2359-60
Laskowski, Igor A; Pratschke, Johann; Wilhelm, Marcus M et al. (2002) Early and late injury to renal transplants from non-heart-beating donors. Transplantation 73:1468-73
Pratschke, J; Wilhelm, M J; Laskowski, I et al. (2001) The influence of donor brain death on long-term function of renal allotransplants in rats. Transplant Proc 33:693-4
Wilhelm, M J; Pratschke, J; Paz, D M et al. (2001) Donor hypertension and recipient immune responsiveness in chronic rat cardiac allograft rejection. Transplant Proc 33:321-2
Tilney, N L; Paz, D; Ames, J et al. (2001) Ischemia-reperfusion injury. Transplant Proc 33:843-4
Laskowski, I A; Pratschke, J; Wilhelm, M J et al. (2001) Prolongation of survival and preservation of allograft structure and function by a signaling CD28 mAB in a rat model of chronic kidney rejection. Transplant Proc 33:567-8

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