Title

Graft-versus-host responses by donor cell populations with impaired cytotoxic function after MHC-mismatched allogeneic bone marrow transplantation

Date of Award

2001

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Robert B. Levy, Committee Chair

Abstract

GVHD remains one of the major obstacles for clinical application of bone marrow transplantation therapy. The aim of this dissertation was to study the involvement of anti-host cytotoxic function in this disease process. To accomplish this, donor T cells with impaired cytotoxic function were employed. Using an MHC I/II mismatched murine BMT model (C57BL/6 → BALB/c), donor T cells from mice simultaneously lacking both Fas ligand and perforin function (B6-cdd) were examined for their capacity to induce graft-versus-host (GVH) responses in lethally irradiated allogeneic recipients. Donor B6-cdd T cells were able to induce remarkable lethal GVHD, with a delayed kinetic pattern compared to equivalent numbers of wild type C57BL/6 (B6-wt) T cells. Approximately 10-fold greater numbers of B6cdd T cells was required to generate comparable kinetics of disease onset. B6-cdd T cell-induced GVH reactions affected target tissues including skin, intestine, stomach and lung, which were also similar to B6-wt T cell induced GVH reactions.When enriched CD4+ donor T cells were used, the kinetic onset was also delayed in the recipients of B6-cdd T cells. The results from this dissertation study suggest that cytotoxic function, particularly in CD4 + cells, is critical for overcoming host resistance.In contrast, enriched CD8+ T cells from either B6-wt or B6-cdd donors induced comparable kinetic onset and patterns of clinical signs in the recipients.To examine whether tumor necrosis factor (TNF) could be responsible for these observations, the involvement of TNF function was approached by employing TNF receptor-I knockout mice (TNFR1KO) as recipients. The results indicated that in this "triple cytotoxic effector pathway deficient" model, the absence of TNFR-I pathway did not impede the development of GVHD induced by B6-cdd or B6-wt CD8+ cells. Moreover, no significant differences in serum levels of TNF-alpha were detected between the recipients of B6-wt and B6-cdd T cells using ELISA. These results demonstrate that in the absence of three cytotoxic effector pathways---i.e. perforin/FasL/TNFR-I, graft-versus-host responses leading to weight loss and clinical changes and lethality can occur. Therefore, other cell- or cytokine-mediated pathways are involved in GVH reactions induced following allogeneic BMT. (Abstract shortened by UMI.)

Keywords

Biology, Cell; Health Sciences, Immunology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3015572