The molecular basis of allorecognition assessment of the involvement of peptide

Newton-Nash, Debra K.

doi:10.1016/0198-8859(94)90002-7

Cited by 15 publications

(9 citation statements)

References 74 publications

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“…Experimental models have proved that the host APCs are necessary and sufficient to activate donor T cells and initiate GvHD (11, 14). Donor T cells can recognize alloantigen either on host APC, known as direct antigen presentation (15), or on donor APCs, known as indirect presentation (16). T-cell responses depend on the disparity between the donor and the recipient with regard to HLA (13).…”

Section: Pathophysiology Of Acute Gvhd: a Three-step Model Explainingmentioning

confidence: 99%

Pathophysiology of GvHD and Other HSCT-Related Major Complications

et al. 2017

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For over 60 years, hematopoietic stem cell transplantation has been the major curative therapy for several hematological and genetic disorders, but its efficacy is limited by the secondary disease called graft versus host disease (GvHD). Huge advances have been made in successful transplantation in order to improve patient quality of life, and yet, complete success is hard to achieve. This review assimilates recent updates on pathophysiology of GvHD, prophylaxis and treatment of GvHD-related complications, and advances in the potential treatment of GvHD.

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Section: Pathophysiology Of Acute Gvhd: a Three-step Model Explainingmentioning

confidence: 99%

Pathophysiology of GvHD and Other HSCT-Related Major Complications

et al. 2017

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“…Second, HLA-B * 4403 may present more novel peptides than B * 4402 (28). The role of peptide-mediated T-cell allorecognition has been extensively reported in both human and murine studies (58,59 (33). Thus, selective binding or altered conformation of individual peptides to just one of the allotypes may also contribute to allospecificity (61).…”

Section: Immunodominance In T-cell Alloreactivitymentioning

confidence: 99%

“…Second, HLA-B * 4403 may present more novel peptides than B * 4402 (28). The role of peptide-mediated T-cell allorecognition has been extensively reported in both human and murine studies (58,59). Several mechanisms may account for peptide involvement in alloresponses generated across a B * 4402 versus B * 4403 mismatch (60).…”

Section: Immunodominance In T-cell Alloreactivitymentioning

confidence: 99%

Immunodominance Hierarchies and Gender Bias in Direct TCD8-Cell Alloreactivity

Mifsud

Purcell

Chen

et al. 2008

American Journal of Transplantation

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Allogeneic solid organ transplantation often occurs across multiple donor-recipient HLA mismatches with consequent risk of allograft rejection. However, there is growing evidence that not all HLA mismatches are equivalent in their stimulation of allogeneic T cells making it important to determine which of these might be more significant as predictors of allograft rejection. To this end, we used defined antigen-presenting cell (APC) transfectants expressing single MHC-I allotypes as target cells that could discriminate the relative contribution of individual mismatched MHC-I allotypes to direct T-cell alloreactivity. We demonstrate remarkably reproducible patterns of immunodominance in reactivity across mismatched MHC-I allotypes. These patterns are HLA context-dependent, partly reflecting alloantigenic competition in responder cell responses. In strong alloresponses, we also observed an increased percentage of alloreactive T CD8 cells in female responders, regardless of the stimulator gender, highlighting HLA-independent factors in the potency of the alloresponse. This approach provides a potential measure of specific alloreactive T cells that could be used in clinical practice for selection of donors, assessment of posttransplant outcomes, modulation of immunosuppression and detection of rejection episodes.

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“…GVHD is associated with enhanced LFA-1-mediated adhesion and decreased activity of SHP-1. Graft-versus-host disease (GVHD) is caused mainly by the engagement of alloreactive T cells (2). To investigate the role of alloactivated T cells in ICAM-1 adhesion and SHP-1 activity in mice with GVHD, we performed fully MHC-mismatched allogeneic hematopoietic stem cell transplantations (HCTs).…”

Section: Resultsmentioning

confidence: 99%

“…In patients, alloresponses cause significant treatment-related morbidity and mortality, such as graft-versus-host disease (GVHD) or graft rejection. Alloreactive T cells are largely responsible for these detrimental effects (2). In this context, T cell function depends on integrinmediated adhesion and migration.…”

mentioning

confidence: 99%

SHP-1 Acts as a Key Regulator of Alloresponses by Modulating LFA-1-Mediated Adhesion in Primary Murine T Cells

Sauer

Herbst

Diekmann

et al. 2016

Molecular and Cellular Biology

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cThe clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft-versus-host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed for the activation of integrins such as LFA-1 is poorly understood. Here, we identified a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting. Upon alloactivation, SHP-1 activity is reduced, resulting in an increase in LFA-1 adhesion compared to that for syngeneically activated T cells. The importance of these differential activation properties was further indicated by small interfering RNA ( R ecipient-derived antigen-presenting cells (APCs) are pivotal for the induction of alloresponses (1). In patients, alloresponses cause significant treatment-related morbidity and mortality, such as graft-versus-host disease (GVHD) or graft rejection. Alloreactive T cells are largely responsible for these detrimental effects (2). In this context, T cell function depends on integrinmediated adhesion and migration.The ␤2 integrins are preferentially expressed among the 12 integrins on lymphocytes. Of these, ␣L␤2 (leukocyte functionassociated antigen 1 [LFA-1], also termed CD11a [␣L chain of LFA-1]-CD18 [␤2 chain of LFA-1]) binds to the ligands ICAM-1, -2, and -3 (intracellular adhesion molecules 1, 2, and 3). The ligands ICAM-1 and -2 are expressed on endothelial cells that line blood vessels on the surface of APCs (3). Following the initial adhesive interaction between potentially alloreactive T cells and allogeneic APCs such as dendritic cells (DCs), LFA-1 facilitates the stable formation of the "immunological synapse," which enhances T cell activation and subsequent effector functions (4, 5). Hence, LFA-1 has emerged as an attractive therapeutic target for the treatment of various inflammatory diseases (6). Immunosuppressive effects induced by LFA-1 antagonists are of substantial interest, since ligation of a T cell receptor (TCR) generates intracellular signals leading to activation of LFA-1-mediated cell adhesion, a process termed "inside-out" signaling. So far, the molecular processes underlying the signaling events between TCR activation and LFA-1 clustering are not fully understood. Adaptor proteins such as ADAP have been identified as key molecules in the TCR "inside-out" pathway (7), and their potential influence in T cell alloreactivity has been discussed (8).Here, we identified the protein tyrosine phosphatase (PTP) SHP-1 as a key regulator of LFA-1-mediated adhesion in primary murine T cells, with particular involvement in alloactivation. We demonstrate for the first time in vitro and in vivo that SHP-1 activity is significantly reduced upon alloactivation, resulting in an increase in the allogeneic activation of T cells and their adhesion to major histocompatibility complex (MHC)-mismatched APCs. Furthermore, we found that SHP-1 ex...

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The molecular basis of allorecognition assessment of the involvement of peptide

Cited by 15 publications

References 74 publications

Pathophysiology of GvHD and Other HSCT-Related Major Complications

Pathophysiology of GvHD and Other HSCT-Related Major Complications

Immunodominance Hierarchies and Gender Bias in Direct TCD8-Cell Alloreactivity

SHP-1 Acts as a Key Regulator of Alloresponses by Modulating LFA-1-Mediated Adhesion in Primary Murine T Cells

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