Unique features and clinical importance of acute alloreactive immune responses

Inman, C., Eldershaw, S., Croudace, Joanne, Davies, N., Sharma-Oates, A., Rai, T., Pearce, H., Sirovica, M., Chan, Y., Verma, K., Zuo, J., Nagra, S., Kinsella, F., Nunnick, J., Amel-Kashipaz, R., Craddock, C., Malladi, R. and Moss, P. (2018) Unique features and clinical importance of acute alloreactive immune responses. JCI Insight, 3 (10). pp. 1-16. ISSN 2379-3708 (ONLINE)

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Abstract

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.

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