Title

Characterization of perforin and Fas ligand effector and regulatory T cell functions in allogeneic bone marrow transplantation

Date of Award

2002

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Robert Levy, Committee Chair

Abstract

Graft versus host disease (GVHD) can limit the therapeutic application and potential of bone marrow transplantation (BMT). The mechanisms T cells employ to initiate and effect GVHD responses remain to be precisely defined. The goal of this dissertation project was to examine the functions of two cytotoxic molecules, fas ligand and perforin, in a clinically relevant MHC-matched murine BMT model. To accomplish this, C57BL/6 donor T cells that lacked these two effector pathways (i.e. cytotoxically double deficient; cdd [H-2b]) were utilized and transplanted into various recipients, primarily MHC I/II matched (H-2b) C3H.SW mice.Experimental analysis demonstrated that mice receiving cytotoxically deficient T cells develop acute lethal GVHD sequellae at similar or greater intensity than those receiving T cells from wt mice. Histopathological findings revealed extensive mononuclear infiltrates and moderate to severe cellular atrophy in the GVHD target tissues examined (liver, stomach) in recipients of cdd T cells compared to mild infiltrate and atrophy in recipients of B6-wt T cells. Survival, clinical signs and LHC changes all supported the occurrence of severe acute GVHD in recipients of B6-cdd T cells.Donor B6-cdd T cells lacking fas ligand and perforin were also found to expand continuously upon transfer into MHC-matched irradiated (9.0 Gy) recipients. This pattern is in marked contrast to the typical expansion followed by contraction of B6-wt CD8 T cells following allogeneic BM transplantation. Subsequent studies demonstrated that expansion did not occur following B6-cdd transplant into syngeneic recipients, but only after transplant into mHAg recipients, and under appropriate conditions into MHC disparate recipients. The pronounced expansion of T cells in cdd recipients (particularly CD8) may contribute to their capacity to induce severe GVHD.Findings from cotransplantation studies suggested that syngeneic CD8 +NK1.1- cells could effect regulatory activity, and kinetic analysis suggested that this 'fratricidal' regulation follows initial T cell expansion. This process was most efficient when the putative regulatory cell expressed both fas ligand and perforin. Based on these findings it is proposed that donor CD8 T cell homeostasis following allogeneic BMT is principally maintained by fratricidal donor regulation.

Keywords

Health Sciences, Immunology

Link to Full Text

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