GVHD after haploidentical transplantation: A novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression

Weston P. Miller, Swetha Srinivasan, Angela Panoskaltsis-Mortari, Karnail Singh, Sharon Sen, Kelly Hamby, Taylor Deane, Linda Stempora, Jonathan Beus, Alexa Turner, Caleb Wheeler, Daniel C. Anderson, Prachi Sharma, Anapatricia Garcia, Elizabeth Strobert, Eric Elder, Ian Crocker, Timothy Crenshaw, M. Cecilia T Penedo, Thea WardMingqing Song, John Horan, Christian P. Larsen, Bruce R. Blazar, Leslie S. Kean

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33 Scopus citations

Abstract

We have developed a major histocompatibility complex-defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8 + and CD4+ granzyme B+ effector cells and FoxP3pos/CD27high/CD25pos/CD127low CD4+ T cells. CD8+ cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative pro-file. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL-18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-γ, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulinresistant CD28- CD8+ T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control.

Original languageEnglish (US)
Pages (from-to)5403-5417
Number of pages15
JournalBlood
Volume116
Issue number24
DOIs
StatePublished - Dec 9 2010

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    Miller, W. P., Srinivasan, S., Panoskaltsis-Mortari, A., Singh, K., Sen, S., Hamby, K., Deane, T., Stempora, L., Beus, J., Turner, A., Wheeler, C., Anderson, D. C., Sharma, P., Garcia, A., Strobert, E., Elder, E., Crocker, I., Crenshaw, T., Penedo, M. C. T., ... Kean, L. S. (2010). GVHD after haploidentical transplantation: A novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression. Blood, 116(24), 5403-5417. https://doi.org/10.1182/blood-2010-06-289272