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Blood, 15 July 2001, Vol. 98, No. 2, pp. 390-397
IMMUNOBIOLOGY
Major histocompatibility complex-mismatched allogeneic bone
marrow transplantation using perforin and/or Fas ligand
double-defective CD4+ donor T cells: involvement of
cytotoxic function by donor lymphocytes prior to graft-versus-host
disease pathogenesis
Zhe Jiang,
Eckhard Podack, and
Robert B. Levy
From the Department of Microbiology and Immunology,
University of Miami School of Medicine, Miami, FL.
Experimental allogeneic bone marrow transplantation (BMT) models
using cytotoxic single-deficient (perforin/granzyme or Fas ligand [FasL]) and cytotoxic double-deficient (cdd) CD4+
donor T cells have previously demonstrated roles for both effector pathways in graft-versus-host disease (GVHD). In the present study, the
role of CD4-mediated antihost cytotoxicity in a GVH response is further
examined across a complete major histocompatibility complex class I/II
mismatch. As predicted, a double cytotoxic deficiency resulted in a
clear delay in GVH-associated weight loss, clinical changes, and
mortality. Interestingly, analysis of donor T-cell presence in 5.5-Gy
recipients soon after BMT demonstrated that the double cytotoxic
deficiency resulted in a marked decrease in donor CD4 numbers.
Transplantation of singularly perforin- or FasL-deficient donor
CD4+ T cells demonstrated that the absence of FasL was
responsible for the markedly diminished CD4 number in recipient lymph
nodes and spleens soon after BMT. However, increasing recipient
total body irradiation conditioning (11.0 Gy) abrogated the
decrease in FasL-defective B6-cdd and B6-gld CD4 numbers. Thus, the
decrease was not a result of inherent CD4 defects, but was probably
attributable to host resistance. Consistent with these observations,
transplantation into 11.0-Gy recipients resulted in identical GVH
lethality by equal numbers of B6 wild-type, B6-cdd, and B6-gld
CD4+ T-cell inoculum. In total, the findings indicate that
aggressive host conditioning lessens the requirement for donor
CD4+ cytotoxic function in GVH responses soon after BMT.
The present results thus support the notion of a role for cytotoxic
effector function in donor CD4+ T cells prior to
GVH-induced tissue injury.
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