Prevention of Graft Versus Host Disease by Inactivation of Host Antigen-Presenting Cells

Shlomchik, Warren D.; Couzens, Matthew S.; Tang, Cheng Bi; McNiff, Jennifer M.; Robert, Marie E.; Liu, Jinli; Shlomchik, Mark J.; Emerson, Stephen G.

doi:10.1126/science.285.5426.412

Cited by 1,112 publications

(875 citation statements)

References 22 publications

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“…6A). The donor T-cell-host antigen-presenting cell interaction is essential for triggering of the GVH reaction [40]. Therefore, in the induction phase of the GVH reaction, it is likely that gp49B on host DC interacts with donor T cells via integrin a v b 3 or other unidentified ligand(s), and thereby delivers negative signals into the host DC, and then limits the excessive allogeneic T-cell response.…”

Section: Discussionmentioning

confidence: 99%

“…It is well accepted that the recipient's DC trigger a GVH reaction through interaction with allo-reactive donor CD4 1 and CD8 1 T cells [40]. Thus, to examine the possibility of negative regulation by gp49B in the allogeneic reaction in vivo, we employed a lethal GVH disease model, for which sublethally irradiated gp49B À/À or B6 (H-2 b ) recipient mice received BALB/c (H-2 d ) splenocytes intravenously.…”

Section: Treg-mediated Suppression Of Proliferation Was Not Impairedmentioning

confidence: 99%

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A novel regulatory role of gp49B on dendritic cells in T‐cell priming

et al. 2008

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Dendritic cells (DC) play pivotal roles in the induction and regulation of both innate and acquired immunity. DC express several cell-surface immune inhibitory receptors. However, little is known about their potential immunoregulatory functions in the context of T-cell activation. Here we report that murine gp49B, a member of the immunoglobulin superfamily, harboring immunoreceptor tyrosine-based inhibitory motifs, is expressed on DC and downregulates cellular activity to prevent the excessive activation of T cells in vitro and in vivo. Bone marrow-derived DC (BMDC) from newly generated gp49B-deficient (gp49B À/À ) mice induced enhanced proliferation and IL-2 release of antigen-specific CD4 1 and CD8 1 T cells compared with BMDC from wild-type mice, in a cell-cell contact manner. The enhanced proliferation by gp49B À/À BMDC was also observed in allogeneic CD4 1 and CD8 1 T cells. Moreover, the transfer of allogeneic BALB/c splenocytes into C57BL/6 gp49B À/À mice induced severe acute graft-versus-host disease with an augmented upregulation of CD86 on CD11c 1 splenic gp49B À/À DC, while transfer of C57BL/6 gp49B À/À splenocytes into BALB/c mice did not, suggesting the exacerbation of the disease was due, at least in part, to augmented activation of recipient gp49B À/À DC. These findings demonstrate a novel regulatory role of gp49B in the function of DC.Key words: Antigen presentation Á Costimulation Á DC Á Regulatory receptor Á Tolerance IntroductionDendritic cells (DC) are professional antigen-presenting cells that recognize a diverse repertoire of antigens and present them to naïve T cells for the induction of acquired immunity [1]. DC are also related to innate immunity by producing cytokines such as both type I and II IFN, or by activating NK cells [2,3]. In addition, recent reports revealed that a subset of DC maintains peripheral tolerance in the steady state [4], showing that DC play a pivotal role in the induction of immune responses including autoimmunity.On the DC surface, a variety of structurally different immunoreceptors that regulate DC and T-cell functions have been found, including CD80, CD86, CD40, and various Ig superfamily and lectin family molecules [5]. Among them, a group of paired Ig superfamily receptors, termed Ig-like receptors, have been attracting the interest of many researchers because they are expressed on various subsets of DC and are considered to contribute to the development or activation of DC [6][7][8][9][10]. Generally, Ig-like receptors are subdivided into two types, namely activating and inhibitory receptors, and in some cases they are expressed on hematopoietic cells in a pair-wise manner [11][12][13][14]. Most activating receptors associate with homodimeric subunits containing ITAM, such as the FcR common g chain and KARAP/DAP12 [15,16], and deliver positive signals into the cells through interaction with their ligands [17]. For instance, the uptake of immune complexes through activating FcR for IgG 2426augments DC maturation, leading to efficient antigen presentation [18...

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Section: Discussionmentioning

confidence: 99%

Section: Treg-mediated Suppression Of Proliferation Was Not Impairedmentioning

confidence: 99%

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

et al. 2008

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“…94 42 The resulting CTL response was, in all cases, limited to the haplotype of the immunizing cells, indicating that the efficiency and physiological relevance of cross -priming in vivo are very low or absent. In addition, in an allogeneic bone marrow transplantation model, Shlomchik et al 95 showed that despite the presence of numerous donor APCs, only host -derived APCs presented minor histocompatibility antigens in vivo and initiated graft -versus -host disease. Thus, cross -priming of recipient minor histocompatibility antigens on donor APC was inefficient.…”

Section: Cancer Gene Therapymentioning

confidence: 99%

Principles of tumor immunosurveillance and implications for immunotherapy

Ochsenbein

2002

Cancer Gene Ther

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Although antigen loss variants, major histocompatibility ( MHC ) class I down -regulation, or the expression of inhibitory molecules may explain the failure of immunosurveillance against some tumors, this seems not to apply for many other solid peripheral or lymphohematopoietic tumors. Why then is immunosurveillance so ineffective and can it be improved? This review focuses on one important aspect of tumor immunity, namely the relevance of antigen dose and localization. Immune responses in vivo are induced in organized lymphoid tissues, i.e., in lymph nodes and spleen. The antigen dose that reaches secondary lymphoid organs over time is a crucial parameter that drives antiviral and antitumoral immune responses. Tumors use various strategies to prevent efficient presentation of their antigens in lymphoid organs. A major obstacle to the induction of an endogenous tumor -specific cytotoxic T lymphocyte ( CTL ) response is the inefficient presentation of tumor antigen on MHC class I molecules of professional antigenpresenting cells. Peripheral solid tumors that develop outside lymphoid organs are, therefore, often ignored by the immune system. In other situations, tumors -especially of lymphohematopoietic origin -may tolerize specific CTLs. Understanding tumor immunosurveillance is key to the design of efficient antitumor vaccines. Attempts to improve immunity to tumors include vaccination strategies to ( a ) provide the tumor antigen to secondary lymphoid organs using recombinant viruses or dendritic cells as carriers, ( b ) express costimulatory signals on tumor cells, or ( c ) improve the efficiency of cross -priming.

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“…Nearly two decades ago Korngold and Sprent 2 identified mature donor T cells as the fundamental cellular mediators of GVHD in an MHC matched minor antigenic disparate allogeneic BMT. More recently, the critical role of host 3 and donor 4,5 APCs in the development of GVHD has been established. We now know that the fundamental interaction for induction of GVHD, as it is for all adaptive immune responses, is the interaction of donor T cells with APCs and that this interaction is regulated positively or negatively by a plethora of cytokines, chemokines and several immune cell subsets.…”

Section: Introductionmentioning

confidence: 99%

New perspectives on the biology of acute GVHD

Paczesny

Hanauer

Sun

et al. 2009

Bone Marrow Transplant

158

126

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The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as:(1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

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Prevention of Graft Versus Host Disease by Inactivation of Host Antigen-Presenting Cells

Cited by 1,112 publications

References 22 publications

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

Principles of tumor immunosurveillance and implications for immunotherapy

New perspectives on the biology of acute GVHD

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