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Toxicity and efficacy of anti-T-cell ricin toxin A chain immunotoxins in a
murine model of established graft-versus-host disease induced across the
major histocompatibility barrier
DA Vallera, SF Carroll, DC Snover, GJ Carlson and BR Blazar
Department of Therapeutic Radiology, University of Minnesota Hospital and
Clinic, Minneapolis 55455.
Graft-versus-host disease (GVHD) was induced across the murine major
histocompatibility complex by injecting C57BL/6 (H-2b) bone marrow and
splenocytes into lethally irradiated B10.BR (H-2k) murine recipients. An
immunotoxin (IT) composed of a pan T-cell monoclonal antibody called
anti-Ly1 (the murine homologue to human anti-CD5) was conjugated to ricin
toxin A chain (anti-Ly1-RTA) and used to treat recipient mice. In vitro, IT
was as active as free RTA, bound selectively, and inhibited T- cell
proliferation even in the absence of potentiators. Mice administered
anti-Ly1-RTA in vivo during ongoing GVHD, at a dose of 10 micrograms/d for
5 days, showed lower numbers of splenic Thy1.2+ T cells and significantly
improved survival as compared with mice given phosphate-buffered saline
(PBS) or irrelevant control RTA IT. Protection was transient because GVHD
and weight loss occurred when injections ceased. Survival could not be
enhanced by crosslinking RTA30, a low oligosaccharide-containing fraction
of purified RTA. Treatment with anti-Ly1-RTA caused a significant elevation
in neutrophils, and higher doses were associated with mild hepatotoxicity.
In contrast, infusion of identical doses and schedules of another pan T-
cell immunotoxin, anti-Thy1.2-RTA, caused a significant decrease in
lymphocytes, but not neutrophils; a precipitous increase in weight; a
decrease in total plasma protein (TPP); and an increase in pleural and
peritoneal effusions reminiscent of vascular leak syndrome (VLS). Although
the toxic effects of anti-Thy1.2-RTA were too severe to show a survival
advantage in a GVHD model, histopathologic studies showed a definite
anti-GVHD effect. The most significant decline in GVHD as compared with the
PBS-treated controls was observed in skin, and to a lesser extent, in liver
and lung. To investigate the cause of IT toxicity, anti-Thy1.2-RTA was
administered intraperitoneally to lethally irradiated B10.BR (H-2k)
recipients of syngeneic bone marrow. These recipients showed the same
weight gain, hypoproteinuria, and VLS observed in the GVHD model. Death
occurred at higher anti-Thy1.2-RTA doses (30 or 50 micrograms/daily
injections administered days 8 through 12 posttransplant). Anti-Thy1.2-RTA
had a negligible effect on renal function, but histologic studies showed
patchy dropout of the renal tubules. Treatment resulted in pulmonary
vascular congestion, but there was no pathologic evidence of liver, brain,
or colon toxicity. Weight gain was enhanced by irradiation because
nonirradiated normal mice did not undergo such a precipitous weight
increase.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 77,
Issue 1,
pp. 182-194,
01/01/1991
Copyright © 1991 by The American Society of Hematology
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