We evaluated the inhibitory effects of two immunotoxins (IT) synthesized by linking two different anti-CD2 (T, p50) murine monoclonal antibodies (MoAb) to intact ricin (R). Pretreatment with 1000 ng ml-1 35.1-R or OKT 11a R inhibited PHA-induced T-cell proliferation by 93% and 86%, respectively. At this IT concentration generation of alloreactive cytotoxic T-cells (CTL) was inhibited by more than 99% by either IT. 35.1-R and OKT 11a were minimally toxic to natural killer (NK) effectors or pluripotent bone marrow progenitor cells (CFU-GEMM). Blocking experiments suggested that 35.1-R and OKT 11a-R might recognize different epitopes of the CD2 (T, p50) surface determinant. Our findings show that anti-CD2 IT may be useful for T-cell depletion in allogeneic bone marrow transplantation. We compared TU3, an equimolar mixture of T101 [anti-CD5]-R, UCHT-1 [anti-CD3]-R and 35.1 [anti-CD2]-R with the TUT-cocktail (a mixture of T101-R, UCHT-1-R and TA-1 [antiCDwl8]-R. TUT is currently under evaluation in Phase 1 clinical trials as a T-cell depletion regimen for GVHD prophylaxis. TU3 was as effective as TUT-cocktail in inhibition of PHA response and CTL generation but unlike TUT spared NK effectors. Cocktails of immunotoxins directed against subpopulations of lymphocytes may be useful (a) for more effective anti-GVHD strategies, and (b) to circumvent problems of graft failure/rejection associated with current purgation regimens.
Bibliographical noteFunding Information:
GRAFT-vs-host disease (GVHD), which is initiated by a reaction of donor T-cells against host histocompatibility antigens, is a major obstacle to the successful therapeutic outcome of allogeneic bone marrow transplantation (BMT) \[17, 24, 25\]. In murine BMT models it has been shown that elimination of donor T-cells from allogeneic bone marrow grafts protects recipients from lethal GVHD \[9, 16, 28, 31, 32\]. Based on these ex- *This work was supported in part by NCI grants CA-31618 and CA-36725. Also by the American Cancer Society grant IM-380 and the Minnesota Medical Foundation grant SMF-320-82. D.A Vallera is a Scholar of the Leukemia Society of America. F. M. Uck un is a Scholar of Tubitak. CETCR publication 6.
- Allogeneic bone marrow transplantation
- T-cell depletion
- graft vs host disease