CD28-Specific Antibody Prevents Graft-Versus-Host Disease in Mice

Yu, Xue-Zhong; Bidwell, Sasha J.; Martin, Paul J.; Anasetti, Claudio

doi:10.4049/jimmunol.164.9.4564

Cited by 90 publications

(79 citation statements)

References 37 publications

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“…In contrast, allogeneic proliferation involves activation of T cells bearing TCRs with a wide range of affinities for different allo-MHC/antigens. Furthermore, lower affinity interactions between TCR and allo-MHC/ antigen play a crucial role in GVHD induction (31,32). Thus, a possible explanation for impaired allogeneic proliferation of PKCθ -/-T cells may be that they respond poorly to lower affinity TCR agonists.…”

Section: Strength Of Tcr Stimulation Determines the Requirement Formentioning

confidence: 99%

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

Valenzuela¹,

Iclozan²,

Hossain³

et al. 2009

J. Clin. Invest.

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When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graftversus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform θ (PKCθ), a key regulator of TCR signaling. In contrast, PKCθ was required for alloreactivity and GVHD induction. Furthermore, absence of PKCθ raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCθ-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCθ is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.

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Section: Strength Of Tcr Stimulation Determines the Requirement Formentioning

confidence: 99%

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

Valenzuela¹,

Iclozan²,

Hossain³

et al. 2009

J. Clin. Invest.

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“…Our protocol for T cell purification and transplantation has been described in detail (24,25). Briefly, CD4 ϩ or CD8 ϩ T cells were purified by positive selection with a magnetic cell separation system (Miltenyi Biotec).…”

Section: T Cell Purification and Transplantationmentioning

confidence: 99%

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Liang

Nurieva

et al. 2006

The Journal of Immunology

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ICOS, a CD28 family member expressed on activated CD4+ and CD8+ T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4+ or CD8+ T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS−/− CD4+ T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS−/− CD4+ T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-γ and TNF-α. Thus, ICOS−/− CD4+ T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS−/− CD8+ T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8+ T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS−/− CD8+ T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4+ and CD8+ T cells in GVHD.

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“…Our protocol for T cell purification and transplantation has been described in detail (3,4). Briefly, CD8…”

Section: T Cell Purification and Transplantationmentioning

confidence: 99%

Anti-CD3ε F(ab′)2 Prevents Graft-Versus-Host Disease by Selectively Depleting Donor T Cells Activated by Recipient Alloantigens

Bidwell

Martin

et al. 2001

The Journal of Immunology

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Transplantation tolerance is facilitated by activation-induced apoptosis of peripheral T cells triggered by specific Ag. Abs specific for the nonpolymorphic CD3 component of the TCR complex bind to APCs through Fc-FcR interactions, mimic MHC-peptide, and activate polyclonal T cells. In contrast, F(ab′)2 of anti-CD3ε Abs do not activate naive T cells but induce apoptosis of Ag-activated, cycling T cells. Here, we report that treatment with anti-CD3ε F(ab′)2 can selectively induce apoptosis of donor T cells that recognize a recipient alloantigen, thereby preventing graft-vs-host disease initiated by a TCR-transgenic T cell population. The selective elimination of Ag-activated T cells by non-FcR-binding anti-CD3ε Abs could serve as an ideal strategy to prevent graft-vs-host disease and allograft rejection or to treat autoimmune disorders.

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CD28-Specific Antibody Prevents Graft-Versus-Host Disease in Mice

Cited by 90 publications

References 37 publications

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Anti-CD3ε F(ab′)2 Prevents Graft-Versus-Host Disease by Selectively Depleting Donor T Cells Activated by Recipient Alloantigens

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