Breaking of CD8+ T Cell Tolerance through In Vivo Ligation of CD40 Results in Inhibition of Chronic Graft-versus-Host Disease and Complete Donor Cell Engraftment

Kim, Juyang; Park, Keunhee; Kim, Hee Jin; Kim, Jiyoung; Kim, Hyun-A.; Jung, Daehee; Kim, Hye J.; Choi, Hye-Jeong; Choi, Suck-Young; Seo, Kwang Won; Cho, Hong R.; Kwon, Byungsuk

doi:10.4049/jimmunol.181.10.7380

Cited by 15 publications

(12 citation statements)

References 65 publications

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“…Activating or maturing DCs by administering agonistic anti-CD40 Abs has been shown to break tolerance (16), and the presence of CD40 on mature APCs has been noted during the initiation of T cell-dependent autoimmune responses (17,18). CD40 activation induces IL-12 production on DCs, resulting in the induction of Th1 responses (19)(20)(21).…”

Section: Ifferent Subsets Of Effector Cd4mentioning

confidence: 99%

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Katzman

Gallo

Hoyer

et al. 2011

The Journal of Immunology

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T cell–APC interactions are essential for the initiation of effector responses against foreign and self-antigens, but the role of these interactions in generating different populations of effector T cells in vivo remains unclear. Using a model of CD4+ T cell responses to a systemic self-antigen without adjuvants or infection, we demonstrate that activation of APCs augments Th17 responses much more than Th1 responses. Recognition of systemic Ag induces tolerance in self-reactive CD4+ T cells, but induction of CD40 signaling, even under tolerogenic conditions, results in a strong, Ag-specific IL-17 response without large numbers of IFN-γ–producing cells. Transfer of the same CD4+ T cells into lymphopenic recipients expressing the self-antigen results in uncontrolled production of IL-17, IFN-γ, and systemic inflammation. If the Ag-specific T cells lack CD40L, production of IL-17 but not IFN-γ is decreased, and the survival time of recipient mice is significantly increased. In addition, transient blockade of the initial MHC class II-dependent T cell–APC interaction results in a greater reduction of IL-17 than of IFN-γ production. These data suggest that Th17 differentiation is more sensitive to T cell interactions with APCs than is the Th1 response, and interrupting this interaction, specifically the CD40 pathway, may be key to controlling Th17-mediated autoimmunity.

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Section: Ifferent Subsets Of Effector Cd4mentioning

confidence: 99%

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Katzman

Gallo

Hoyer

et al. 2011

The Journal of Immunology

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“…There remains a possibility that these T-cells may induce GVHD in conditions where their expansion is promoted by inflammatory triggers. Otherwise, the size of alloreactive donor T-cell pool may not reach a threshold to mediate GVHD, even though it is sufficient for the GVL effect (23). In this aspect, more thorough deletion of alloreactive T-cells at the peak of CD137 expression in an in vitro MLR may result in depletion of donor T-cells having a GVL potential.…”

Section: Discussionmentioning

confidence: 99%

“…To test the effect of allodepletion by the anti-CD137-saporin immunotoxin on the GVL effect following BM transplantation, we used an EL-4 lymphoma model that has been well established by our and other laboratories (23). Recipient C57BL/6 mice were inoculated intravenously with 1 × 10 7 of EL4 cells 7 days before receiving lethal total body irradiation (850 rad).…”

Section: Hsct After Allodepletion With Anti-cd137-saporin Immunotoxinmentioning

confidence: 99%

Depletion of Alloreactive T-Cells by Anti-CD137-Saporin Immunotoxin

et al. 2015

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Depletion of alloreactive T-lymphocytes from allogeneic bone marrow transplants may prevent graft-versus-host disease (GVHD) without impairing donor cell engraftment, immunity, and the graft-versus-leukemia (GVL) effect. Alloreactive T-cells may be identified by their expression, upon activation, of CD137, a costimulatory receptor and putative surrogate marker for antigen-specific effector T-cells. In this context, we tested the use of anti-CD137-saporin immunotoxin to selectively deplete mouse and human alloreactive T-cells. Anti-CD137 antibodies were internalized by cells within 4 h of binding to the cell surface CD137, and anti-CD137-saporin immunotoxin effectively killed polyclonally activated T-cells or antigen-stimulated T-cells. Transfer of donor T-cells after allodepletion with anti-CD137-saporin immunotoxin failed to induce any evident expression of GVHD; however, a significant GVL effect was observed. Targeting of CD137 with an immunotoxin was also effective in killing polyclonally activated or alloreactive human T-cells. Our results indicate that anti-CD137-saporin immunotoxin may be used to deplete alloreactive T-cells prior to bone marrow transplantation and thereby prevent GVHD and the relapse of leukemia.

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“…In the DBA/2→unirradiated BDF1 SLE-like cGVHD model, ligation of CD40 prevents the evolution of cGVHD (Kim et al, 2008;Puliaev et al, 2008).…”

Section: Cd40 and Gitrmentioning

confidence: 99%

Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease

Kwon

2010

Exp Mol Med

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Graft-versus-host disease (GVHD) is mediated by mature donor T cells contained in the hematopoietic stem cell graft. During the development of GVHD, signaling through a variety of costimulatory receptors plays an important role in allogeneic T cell responses. Even though delivery of costimulatory signals is a prerequisite for full activation of donor T cells in the phase of their interactions with host APCs, their involvement with GVHD might occur over multiple stages. Like many other aspects of GVHD, promise of therapeutic interventions with costimulatory pathways has been gleaned from preclinical models. In this review, I summarize some of the advances in roles of costimulatory molecules in GVHD pathophysiology and discuss preclinical approaches that warrant further exploration in the clinic, focusing on novel strategies to delete pathogenic T cells.

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Breaking of CD8+ T Cell Tolerance through In Vivo Ligation of CD40 Results in Inhibition of Chronic Graft-versus-Host Disease and Complete Donor Cell Engraftment

Cited by 15 publications

References 65 publications

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Depletion of Alloreactive T-Cells by Anti-CD137-Saporin Immunotoxin

Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease

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