Title

Development and characterization of a model to study modulation of graft-versus-host reactions by pathogens: Exacerbation of class I MHC disparate GvHR by concurrent MCMV infection depends on distinct subsets of donor and host T cells

Date of Award

1990

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Robert B. Levy, Committee Chair

Abstract

Infection by cytomegalovirus in bone marrow transplant recipients has been correlated with the onset of graft-versus-host disease. To determine the consequences of viral infection on graft-versus-host reactions (GvHR), murine cytomegalovirus (MCMV) infection was given concurrently to F$\sb1$ recipients of parental strain lymphoid cells. It was determined that concurrent MCMV infection greatly enhanced GvH reactions across class I MHC donor-recipient disparity. Importantly, this same affect was observed when a class I and II MHC difference was present but not in GvH reactions across class II MHC disparity. In examination of the affect of virus on the class I GvHR, it was determined that MCMV infection resulted in the exacerbation of the reaction. Several alterations associated with severe GvHR were induced: phenotypic alterations in T-cell populations in the thymus and spleen, in vitro unresponsiveness of spleen cells, donor T-cell chimerism in the recipient spleen, "GvHR appearance" (i.e. weight loss and mortality), and anti-host cytotoxic activity.In subsequent experiments, the effect of virus was found to be unusual as the injection of either an inactivated preparation of MCMV or the T-dependent antigen DNP-BSA concurrent with donor cells did not result in the exacerbation of the GvH reaction. Studies revealed that recipients of virus and donor cells produce a primary IgM antibody response and exhibit an elevation in NK cytotoxic activity. Experiments using depletion of specific donor and host T-cell subsets and NK cells showed that donor CD8+ cells and host cells were required for the viral exacerbation of the class I GvHR which is consistent with a hypothesis that the virus induces immune responses by host CD4+ cells which serve to augment the GvHR. In total, the dissertation research has demonstrated that when only a class I MHC disparity exists between donor and recipient, viral infection can alter the normally mild GvHR to produce a very severe GvH reaction implying that viral infection after bone marrow transplants across class I HLA or class I HLA allelic variant differences can have a marked effect on the subsequent GvH reaction and disease.

Keywords

Biology, Cell; Health Sciences, Medicine and Surgery; 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:9114793