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In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces
lethal murine graft-versus-host disease across the major histocompatibility
complex barrier in mice
BR Blazar, PA Taylor, PS Linsley and DA Vallera
Department of Pediatrics, University of Minnesota Hospital and Clinic,
Minneapolis.
We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused
with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell
costimulation, could prevent efficient T-cell activation and thereby reduce
graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of
major histocompatibility complex disparate C57BL/6 donor grafts received
intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig
(mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of
bone marrow transplantation (BMT). In all five experiments, recipients of
CTLA4-Ig had a significantly higher actuarial survival rate compared to
mice injected with an irrelevant antibody control (L6) or saline alone.
Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days
post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63%
mice surviving 3 months post-BMT. However, protection was somewhat variable
and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical
appearance, and histopathologic examination. There were no significant
differences in the survival rates in comparing injection dose, injection
duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4- Ig). Splenic and
peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected
survivors showed a significant peripheral B-cell and CD4+ T-cell
lymphopenia, consistent with GVHD. A kinetic study of splenic
reconstitution was performed in mice that received hCTLA4-Ig and showed
that mature splenic localized CD8+ T-cell repopulation was not
significantly different in recipients of hCTLA4-Ig compared with hL6,
despite the significant increase in actuarial survival rate in that
experiment. These data suggest that the beneficial effect of hCTLA4-Ig on
survival is not mediated by interfering with mature donor- derived T-cell
repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with
hematopoietic recovery post-BMT. We conclude that CTLA4- Ig (most likely in
combination with other agents) may represent an important new modality for
GVHD prevention.
Volume 83,
Issue 12,
pp. 3815-3825,
06/15/1994
Copyright © 1994 by The American Society of Hematology
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