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.
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.
Miller
Weston P
WP
Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Srinivasan
Swetha
S
Panoskaltsis-Mortari
Angela
A
Singh
Karnail
K
Sen
Sharon
S
Hamby
Kelly
K
Deane
Taylor
T
Stempora
Linda
L
Beus
Jonathan
J
Turner
Alexa
A
Wheeler
Caleb
C
Anderson
Daniel C
DC
Sharma
Prachi
P
Garcia
Anapatricia
A
Strobert
Elizabeth
E
Elder
Eric
E
Crocker
Ian
I
Crenshaw
Timothy
T
Penedo
M Cecilia T
MC
Ward
Thea
T
Song
Mingqing
M
Horan
John
J
Larsen
Christian P
CP
Blazar
Bruce R
BR
Kean
Leslie S
LS
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*
D018106:CD28 Antigens; D020123:Sirolimus