An Antibody Combination That Targets Activated T Cells Extends Graft Survival in Sensitized Recipients

• Published in: American journal of transplantation Vol. 8; no. 11; pp. 2272 - 2282
• Main Authors: Greenlaw, R. E., Gardner, N. J., Farrar, C. A., Shariff, H., Sacks, S. H., Yagita, H., Simpson, E., Jurcevic, S.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01-11-2008; Blackwell
• Subjects: Animals; Antibody therapy; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Movement; Female; Graft Survival; Immunologic Memory; Lymphocyte Activation; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotype; sensitized recipients; Spleen - cytology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes - metabolism; transplantation immunology; T‐cell memory; Human; Cell survival; Antibody; Memory; Recipient; Transplantation; Homotransplantation; T-cell memory; transplantation immunology; Immunology; Treatment; sensitized recipients; Surgery; T-Lymphocyte; Graft; Sensitization; Target cell; Antibody therapy
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2008.02393.x

Memory T cells are the very essence of adaptive immunity with their rapid and efficient response to antigen rechallenge and long‐term persistence. However, it is becoming increasingly evident that when primed with self or transplanted tissue, these cells play a key role in causing and perpetuating tissue damage. Furthermore, current treatments, which efficiently control the naive response, have limited effects on primed T cells. We have used a treatment based on a combination of antibodies specific for molecules expressed by activated T lymphocytes to selectively remove these cells. This approach, which we termed multi‐hit therapy, leads to cumulative binding of antibodies to the target T cells and a striking prolongation of skin graft survival in presensitized recipients in a stringent skin transplant model. The findings are consistent with the depletion of graft‐specific CD4+ and CD8+ T cells, although other modes of action, such as T‐cell regulation and altered migration could play a role. In conclusion, our therapeutic strategy controls primed T cells which are a major driving force in the pathology of many autoimmune diseases and in transplant rejection.
A combination of CD154‐, CD70‐ and CD8‐specific antibodies plus short‐term rapamycin therapy acts synergistically to remove activated T cells and achieves impressive graft survival in a stringent, pre‐sensitized skin transplant model.