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

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