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Ex Vivo Anti-CD3 Antibody-Activated Donor T Cells Have a Reduced Ability to Cause Lethal Murine Graft-Versus-Host Disease but Retain Their Ability to Facilitate Alloengraftment¹

William R. Drobyski^2,*, David Majewski^*, Kutlan Ozker and Gerald Hanson

Departments of ^* Medicine, Radiology, and Pathology, and Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226

The purpose of this study was to determine whether ex vivo anti-CD3 Ab-activated T cells behaved in a biologically similar manner as naive T cells with respect to causing graft-vs-host disease (GVHD) and facilitating engraftment after allogeneic marrow transplantation. This question was addressed using two well-defined MHC-incompatible murine models of GVHD (C57BL/6 (H-2^b)B10.BR (H-2^k)) and engraftment (C57BL/6 (H-2^b)AKR/J (H-2^k)). Transplantation with anti-CD3-activated T cells significantly reduced GVHD compared with that in animals transplanted with equivalent numbers of naive T cells. Protection from GVHD was not T cell subset dependent, as highly enriched populations of either activated CD4⁺ or CD8⁺ T cells caused less lethal GVHD than comparable numbers of purified naive CD4⁺ or CD8⁺ T cells. Transplantation with activated T cells also resulted in protection from LPS-mediated GVH lethality in unirradiated F₁ recipients. Analysis of immune recovery indicated that animals transplanted with activated T cells had thymic and splenic B cell reconstitution that compared favorably to that in non-GVHD control mice. When engraftment was analyzed, equivalent degrees of donor cell engraftment were observed when animals were transplanted with limiting numbers (5 x 10⁵) of naive vs activated B6 T cells. Further studies indicated that activated CD8⁺ T cells were exclusively responsible for enhancing engraftment and that facilitation of engraftment was dependent upon the direct recognition of host MHC alloantigens. Collectively, these data demonstrate that transplantation with anti-CD3 Ab-activated T cells results in a reduction in GVHD, but these cells retain their ability to facilitate alloengraftment. The use of this approach in allogeneic marrow transplantation may represent an alternative strategy to mitigate GVHD without compromising engraftment.

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