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"Pruning" of Alloreactive CD4⁺ T Cells Using 5- (and 6-)Carboxyfluorescein Diacetate Succinimidyl Ester Prolongs Skin Allograft Survival¹

Debbie Watson^*, Geoff Yu Zhang^*, Mary Sartor and Stephen I. Alexander^2,*

^* Center for Kidney Research, The Children’s Hospital at Westmead; and Westmead Institute of Cancer Research, Westmead Hospital, Westmead, New South Wales, Australia

Removal of alloreactive cells by either thymic deletion or deletion/anergy in the periphery is regarded as crucial to the development of tolerance. Dyes, such as CFSE, that allow monitoring of cell division suggest that in vitro proliferation could be a used as a way of "pruning" alloreactive cells while retaining a normal immune repertoire with retention of memory to previously encountered pathogens. This would overcome the problems occurring as a result of therapies that use massive depletion of T cells to allow acceptance of organ transplants or bone marrow grafts. We therefore used a skin graft model of CD4-mediated T cell rejection across a major H-2 mismatch (C57BL/6 (H-2^b) to BALB/c (H-2^d) mice) to evaluate whether nondividing CD4⁺ T cells derived from a mixed lymphocyte culture would exhibit tolerance to a skin graft from the initial stimulator strain. We demonstrate that selective removal of dividing alloreactive CD4⁺ T cells resulted in marked specific prolongation of allogeneic skin graft survival, and that the nondividing CD4⁺ T cells retained a broad TCR repertoire and the ability to maintain memory. This novel way of depleting alloreactive T cells may serve as a useful strategy in combination with other mechanisms to achieve transplant tolerance.

This article has been cited by other articles:

				M. Hu, D. Watson, G. Y. Zhang, N. Graf, Y. M. Wang, M. Sartor, B. Howden, J. Fletcher, and S. I. Alexander Long-Term Cardiac Allograft Survival across an MHC Mismatch after "Pruning" of Alloreactive CD4 T Cells J. Immunol., May 15, 2008; 180(10): 6593 - 6603. [Abstract] [Full Text] [PDF]