title: 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.
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 FoxP3(pos)/CD27(high)/CD25(pos)/CD127(low) CD4(+) T cells. CD8(+) cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. 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 immunoglobulin-resistant CD28(-) CD8(+) T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control.
authors.affiliation: Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Weston P
authors.initials: WP
authors.lastname: Miller
authors.forename: Swetha
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Karnail
authors.initials: K
authors.lastname: Singh
authors.forename: Sharon
authors.initials: S
authors.lastname: Sen
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamby
authors.forename: Taylor
authors.initials: T
authors.lastname: Deane
authors.forename: Linda
authors.initials: L
authors.lastname: Stempora
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beus
authors.forename: Alexa
authors.initials: A
authors.lastname: Turner
authors.forename: Caleb
authors.initials: C
authors.lastname: Wheeler
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anderson
authors.forename: Prachi
authors.initials: P
authors.lastname: Sharma
authors.forename: Anapatricia
authors.initials: A
authors.lastname: Garcia
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Strobert
authors.forename: Eric
authors.initials: E
authors.lastname: Elder
authors.forename: Ian
authors.initials: I
authors.lastname: Crocker
authors.forename: Timothy
authors.initials: T
authors.lastname: Crenshaw
authors.forename: M Cecilia T
authors.initials: MC
authors.lastname: Penedo
authors.forename: Thea
authors.initials: T
authors.lastname: Ward
authors.forename: Mingqing
authors.initials: M
authors.lastname: Song
authors.forename: John
authors.initials: J
authors.lastname: Horan
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
mesh_terms: D000818:Animals; D018106:CD28 Antigens; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D007165:Immunosuppression Therapy / Q000379:methods*; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D020123:Sirolimus / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D018106:CD28 Antigens; D020123:Sirolimus