Journal
BLOOD
Volume 98, Issue 2, Pages 390-397Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.V98.2.390
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Funding
- NCI NIH HHS [CA80228, CA57904, CA39201] Funding Source: Medline
- NCRR NIH HHS [1RO1 RR11576] Funding Source: Medline
- NHLBI NIH HHS [5RO1 HL52461] Funding Source: Medline
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Experimental allogeneic bone marrow transplantation (BMT) models using cytotoxic single-deficient (perform/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-Cmediated 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 Fast 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 Fast-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. (C) 2001 by The American Society of Hematology.
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