The use of an anti-TCRαβ monoclonal antibody to control host-versus- graft reactions in canine marrow allograft recipients conditioned with low dose total body irradiation

Alexander A. Barsoukov, Peter F Moore, Rainer Storb, Erlinda B. Santos, Brenda M. Sandmaier

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background. A limitation in the application of marrow transplantation has been complications related to the conditioning regimens that have been intensified to the point where organ toxicities have been common, resulting in morbidity and mortality. Methods. A conditioning regimen consisting of low-dose total body irradiation (TBI(*)) was used to test whether postgrafting therapy with a monoclonal antibody (mAb) against the T cell receptor (TCR)αβ facilitated sustained engraftment of marrow from dog leukocyte antigen (DLA)-identical canine littermates. The anti-TCRαβ mAb 15.9D5 was selected for in vivo studies because it induced hyporesponsiveness to allogeneic stimulator cells in mixed leukocyte culture and was not mitogenic in vitro. Results. When recipients of genotypically DLA-identical marrow were conditioned by the barely 'lethal' dose of 450 cGy TBI alone, almost 60% of grafts failed (n=39). The remainder engrafted, either in the form of stable mixed donor/host or all donor hematopoietic chimerism. In contrast to results in controls, 5 of 6 dogs that were given, in addition, a loading dose of mAb 15.9D5 of 1 mg/kg on day -1,450 cGy TBI on day 0, followed by mAb at 0.3 mg/kg/day until day +7, showed sustained engraftment (P=.058). To accomplish a comparable rate of engraftment in the absence of anti-TCRαβ antibody, 920 cGy TBI were needed for pretransplant conditioning. Conclusions. Results strongly suggested that in vivo administration of a mAb against TCRαβ prevented rejection of allogeneic marrow grafts in the setting of conditioning with a relatively nontoxic but otherwise suboptimal dose of 450 cGy TBI. In vivo administration of mAb 15.9D5 was well tolerated without any noticeable side effects. The exact mechanism by which the mAb works in vivo is as yet poorly understood, but it does not involve CD3/TCR complex modulation or elimination of T cells from the circulation.

Original languageEnglish (US)
Pages (from-to)1329-1335
Number of pages7
JournalTransplantation
Volume67
Issue number10
DOIs
StatePublished - May 27 1999

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Whole-Body Irradiation
T-Cell Antigen Receptor
Allografts
Canidae
Bone Marrow
Monoclonal Antibodies
Transplants
Dogs
HLA Antigens
Chimerism
Thomsen-Friedenreich antibodies
Leukocytes
Transplantation
Morbidity
T-Lymphocytes
Mortality
Antibodies

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

The use of an anti-TCRαβ monoclonal antibody to control host-versus- graft reactions in canine marrow allograft recipients conditioned with low dose total body irradiation. / Barsoukov, Alexander A.; Moore, Peter F; Storb, Rainer; Santos, Erlinda B.; Sandmaier, Brenda M.

In: Transplantation, Vol. 67, No. 10, 27.05.1999, p. 1329-1335.

Research output: Contribution to journalArticle

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abstract = "Background. A limitation in the application of marrow transplantation has been complications related to the conditioning regimens that have been intensified to the point where organ toxicities have been common, resulting in morbidity and mortality. Methods. A conditioning regimen consisting of low-dose total body irradiation (TBI(*)) was used to test whether postgrafting therapy with a monoclonal antibody (mAb) against the T cell receptor (TCR)αβ facilitated sustained engraftment of marrow from dog leukocyte antigen (DLA)-identical canine littermates. The anti-TCRαβ mAb 15.9D5 was selected for in vivo studies because it induced hyporesponsiveness to allogeneic stimulator cells in mixed leukocyte culture and was not mitogenic in vitro. Results. When recipients of genotypically DLA-identical marrow were conditioned by the barely 'lethal' dose of 450 cGy TBI alone, almost 60{\%} of grafts failed (n=39). The remainder engrafted, either in the form of stable mixed donor/host or all donor hematopoietic chimerism. In contrast to results in controls, 5 of 6 dogs that were given, in addition, a loading dose of mAb 15.9D5 of 1 mg/kg on day -1,450 cGy TBI on day 0, followed by mAb at 0.3 mg/kg/day until day +7, showed sustained engraftment (P=.058). To accomplish a comparable rate of engraftment in the absence of anti-TCRαβ antibody, 920 cGy TBI were needed for pretransplant conditioning. Conclusions. Results strongly suggested that in vivo administration of a mAb against TCRαβ prevented rejection of allogeneic marrow grafts in the setting of conditioning with a relatively nontoxic but otherwise suboptimal dose of 450 cGy TBI. In vivo administration of mAb 15.9D5 was well tolerated without any noticeable side effects. The exact mechanism by which the mAb works in vivo is as yet poorly understood, but it does not involve CD3/TCR complex modulation or elimination of T cells from the circulation.",
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