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, Cecilia Penedo, Thea Ward & 5 others Mingqing Song, John Horan, Christian P. Larsen, Bruce R. Blazar, Leslie S. Kean

Research output: Contribution to journalArticle

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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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Transplantation (surgical)
T-cells
Cell proliferation
Graft vs Host Disease
Sirolimus
Macaca mulatta
Grafts
Immunosuppression
Transplantation
Cell Proliferation
T-Lymphocytes
CTLA-4 Antigen
Activation Analysis
Interleukin-23
Chemical activation
Granzymes
Interleukin-18
Interleukin-1 Receptors
Disease control
Activation analysis

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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

In: Blood, Vol. 116, No. 24, 09.12.2010, p. 5403-5417.

Research output: Contribution to journalArticle

Miller, WP, Srinivasan, S, Panoskaltsis-Mortari, A, Singh, K, Sen, S, Hamby, K, Deane, T, Stempora, L, Beus, J, Turner, A, Wheeler, C, Anderson, DC, Sharma, P, Garcia, A, Strobert, E, Elder, E, Crocker, I, Crenshaw, T, Penedo, C, Ward, T, Song, M, Horan, J, Larsen, CP, Blazar, BR & Kean, LS 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, vol. 116, no. 24, pp. 5403-5417. https://doi.org/10.1182/blood-2010-06-289272
Miller, Weston P. ; Srinivasan, Swetha ; Panoskaltsis-Mortari, Angela ; Singh, Karnail ; Sen, Sharon ; Hamby, Kelly ; Deane, Taylor ; Stempora, Linda ; Beus, Jonathan ; Turner, Alexa ; Wheeler, Caleb ; Anderson, Daniel C. ; Sharma, Prachi ; Garcia, Anapatricia ; Strobert, Elizabeth ; Elder, Eric ; Crocker, Ian ; Crenshaw, Timothy ; Penedo, Cecilia ; Ward, Thea ; Song, Mingqing ; Horan, John ; Larsen, Christian P. ; Blazar, Bruce R. ; Kean, Leslie S. / 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. In: Blood. 2010 ; Vol. 116, No. 24. pp. 5403-5417.
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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.",
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T2 - 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

AU - Miller, Weston P.

AU - Srinivasan, Swetha

AU - Panoskaltsis-Mortari, Angela

AU - Singh, Karnail

AU - Sen, Sharon

AU - Hamby, Kelly

AU - Deane, Taylor

AU - Stempora, Linda

AU - Beus, Jonathan

AU - Turner, Alexa

AU - Wheeler, Caleb

AU - Anderson, Daniel C.

AU - Sharma, Prachi

AU - Garcia, Anapatricia

AU - Strobert, Elizabeth

AU - Elder, Eric

AU - Crocker, Ian

AU - Crenshaw, Timothy

AU - Penedo, Cecilia

AU - Ward, Thea

AU - Song, Mingqing

AU - Horan, John

AU - Larsen, Christian P.

AU - Blazar, Bruce R.

AU - Kean, Leslie S.

PY - 2010/12/9

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N2 - 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.

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