Genetic influences on the development of chronic graft -versus -host disease
Abstract
The purpose of this study was to investigate whether the development of chronic graft-versus-host disease (GVHD) is under genetic control in the parent into B6D2F1 murine transplantation model. In this model, it is known that if lymphoid cells from a DBA/2 mouse are injected into a B6D2F1 recipient, the recipient develops chronic GVHD, characterized by elevated serum levels of anti-nuclear autoantibodies and glomerulonephritis. However, if lymphoid cells from a C57BL/6 or C57BL/10 mouse are injected into a B6D2F1 recipient, the recipient develops acute GVHD, characterized by diarrhea and weight loss. This suggested that the development of chronic GVHD is influenced by the genetic makeup of the donor. It was first hypothesized that this differential disease progression was due to the major histocompatibility (MHC) antigenic differences of the donors because the DBA/2 strain possesses the “d” haplotype and the C57BL/6 and C57BL/10 strains have the “b” haplotype. However, lymphoid cells from a MHC congenic mouse, B10.D2, were injected into a B6D2F1 recipient. This congenic mouse is genetically identical to a C57BL/10 mouse except at the MHC, where it possesses the “d” haplotype. It was shown that the recipients of B10.D2 lymphoid cells develop acute GVHD. This suggested that genes other than those encoding the MHC antigens are influencing the development of GVHD in this model. To determine the non-MHC genes influencing disease progression in this model a mapping study was initiated. Since chronic GVHD is characterized by production of anti-nuclear autoantibodies, the levels of antibodies against single stranded DNA (anti-ssDNA antibodies) were used as a phenotype on which to base the mapping study. In this study, simple sequence repeat polymorphism linkage analysis was performed to identify loci influencing levels of anti-ssDNA antibodies in recipient mice. Linkage to two loci, on chromosomes four and eleven, was suggested. Preliminary assessment of three candidate genes, genes encoding CD30, TNFR2 and 4-1BB, was performed. CD30, TNFR2 and 4-1BB are expressed during GVHD and CD30 is polymorphic between the DBA/2 and C57BL/10 strains.
Degree
Ph.D.
Advisors
Allen, Purdue University.
Subject Area
Immunology|Genetics|Surgery
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