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Unique features and clinical importance of acute alloreactive immune responses
Charlotte F. Inman, … , Ram Malladi, Paul Moss
Charlotte F. Inman, … , Ram Malladi, Paul Moss
Published May 17, 2018
Citation Information: JCI Insight. 2018;3(10):e97219. https://doi.org/10.1172/jci.insight.97219.
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Research Article Hematology Immunology

Unique features and clinical importance of acute alloreactive immune responses

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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.

Authors

Charlotte F. Inman, Suzy A. Eldershaw, Joanne E. Croudace, Nathaniel J. Davies, Archana Sharma-Oates, Tanuja Rai, Hayden Pearce, Mirjana Sirovica, Y.L. Tracey Chan, Kriti Verma, Jianmin Zuo, Sandeep Nagra, Francesca Kinsella, Jane Nunnick, Rasoul Amel-Kashipaz, Charles Craddock, Ram Malladi, Paul Moss

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Figure 1

Circulating differentiated allograft and autograft T cells are detectable at week 2 after SCT.

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Circulating differentiated allograft and autograft T cells are detectabl...
(A) Number of T cells/ml of whole blood at week 2 after allo-SCT (n = 50) and auto-SCT (n = 22) and, for comparison, that in healthy donors (HDs; n = 6). Error bars represent SEM. (B) Representative flow cytometric plots demonstrating the presence of CD4 and CD8 T cell populations in an allo-SCT patient and an auto-SCT patient at week 2 after SCT, and in a HD for comparison, that can be further differentiated by their expression of CCR7 and CD45RA (CD4 and CD8). (C) Comparison of the relative proportions of the naive, central memory (CM), effector memory (EM), and effector memory RA–positive (EMRA) phenotypes in CD4 and CD8 T cells at week 2 after allo-SCT (n = 41 CD4, n = 35 CD8) and auto-SCT (n = 37) and, for comparison, HDs (n = 5). Data were analyzed using a Kruskal-Wallis test with Dunn’s multiple comparisons tests, *P < 0.05, **P < 0.01, ***P < 0.001. Error bars represent SEM.

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ISSN 2379-3708

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