A Novel Mechanism for the Immunomodulatory Functions of Class II MHC–Derived Peptides

Murphy, Barbara; Yu, Joyce E.; Jiao, Qingsheng; Lin, Marvin; Chitnis, Tanuja; Sayegh, Mohamed H.

doi:10.1097/01.asn.0000057541.69641.f8

Cited by 8 publications

(14 citation statements)

References 38 publications

(43 reference statements)

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“…HLA-DQA1 requires the interaction of T cells and antigenpresenting cells (APC) for its inhibitory action on T cells. HLA-DQA1 peptide induced apoptosis in B cells, macrophages (20), and dendritic cells (our unpublished observations) via a nonclassical, caspase-independent mechanism. In addition to inducing apoptosis in APC, HLA-DQA1 renders T cells unresponsive to further stimulation.…”

mentioning

confidence: 64%

“…We showed previously that HLA-DQA1 induced apoptosis via a caspase-independent pathway (20). We therefore investigated whether alteration in mitochondrial membrane potential (⌬⌿m) was implicated in apoptosis induced by HLA-DQA1.…”

Section: Hla-dqa1 Peptide Induces Mitochondrial Membrane Depolarizationmentioning

confidence: 99%

“…B cells were separated by nylon wool column from BALB/c splenocytes as described previously (20). B cells (1 ϫ 10 6 ) were incubated in flat-bottomed 24-well plates in the presence or absence of HLA-DQA1 (100 g/ml) or control peptide HLA-DQB1 (100 g/ml).…”

Section: Induction Of Apoptosismentioning

confidence: 99%

“…At this time, cells were spun at 1500 ϫ g and resuspended in 300 l of RNase (50 g/ml) and 300 l of propidium iodide (50 g/ml). Cell-cycle analysis was performed on FACScan as described previously (20).…”

Section: Induction Of Apoptosismentioning

confidence: 99%

“…In addition to inducing apoptosis in APC, HLA-DQA1 renders T cells unresponsive to further stimulation. We have shown that a low dose of HLA-DQA1 prevents the priming of T cells to fully mismatched allogeneic splenocytes and also the response of primed T cells to alloantigen in vivo (20). In this report we investigate the site of binding of HLA-DQA1 and the mechanism by which it mediates apoptosis in APC.…”

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confidence: 97%

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MHC Class II–Mediated Apoptosis by a Nonpolymorphic MHC Class II Peptide Proceeds by Activation of Protein Kinase C

Zang¹,

Kalache²,

Lin³

et al. 2005

Journal of the American Society of Nephrology

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T he interaction of the MHC molecules and their associated antigenic peptides with the T cell receptor is the pivotal step in the cognate response to foreign antigen (1). Synthetic peptides that correspond to polymorphic and nonpolymorphic regions of the MHC molecule have been demonstrated to be effective inhibitors of the allergic, autoimmune, and alloimmune responses in vitro and in vivo (2,3). Immunomodulatory polymorphic peptides that bind within the groove of the MHC molecule may influence the subsequent response of the T cell by altering the recognition of the MHC-peptide complex. Modification of antigenic peptide sequences by a single amino acid has been shown to change the T cell response qualitatively resulting in partial T cell activation and the production of T cell anergy (4,5). The use of these altered peptide ligands has proved to be an effective means of ameliorating autoimmune diseases in small animal models (6,7). In addition, polymorphic MHC classes I and II peptides, which are known to elicit an antigenic response, inhibit the alloimmune response in vivo after administration via oral, intrathymic, and intranasal routes (8 -10). Manipulation of the immune response by modification of known antigenic peptides is limited by the need to identify the specific autoantigens in the case of autoimmune diseases and by an exhaustive number of potential allogeneic peptides in the case of transplantation.Several peptides derived from nonpolymorphic regions of both MHC classes I and II have been shown to inhibit T cell responses in vitro (11). It is interesting that the binding sites and mechanisms of action of these peptides are remarkably different from each other and from that of polymorphic MHC peptides. The inhibitory effect of the nonpolymorphic MHC class I peptides (ALLOTRAP) and their rationally designed analogues correlated with the induction of heme oxygenase-1 and inhibition of TNF-␣ production in vivo (12). These peptides have been shown to prolong survival in several different small animal transplant models (13-15) and modify disease in a murine model of Crohn's disease (16). Boytim et al. (17) demonstrated that a synthetic MHC class II peptide that corresponds to the ␣1 helix of DQA03011 (DQ 65 to 79) inhibits T cell proliferation in an allele-independent manner in vitro through binding to proliferating cell nuclear antigen and competitive inhibition of binding of p21 to proliferating cell nuclear antigen (18). We have shown previously that a peptide, HLA-DQA1, derived from a conserved region of the HLA-DQ ␣ chain (62 to 77), is an efficient inhibitor of the human, rat, and mouse MLR (19). HLA-DQA1 requires the interaction of T cells and antigenpresenting cells (APC) for its inhibitory action on T cells. HLA-DQA1 peptide induced apoptosis in B cells, macrophages (20), and dendritic cells (our unpublished observations) via a nonclassical, caspase-independent mechanism. In addition to inducing apoptosis in APC, HLA-DQA1 renders T cells unresponsive to further stimulation. We have shown that a lo...

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mentioning

confidence: 64%

Section: Hla-dqa1 Peptide Induces Mitochondrial Membrane Depolarizationmentioning

confidence: 99%

Section: Induction Of Apoptosismentioning

confidence: 99%

Section: Induction Of Apoptosismentioning

confidence: 99%

mentioning

confidence: 97%

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MHC Class II–Mediated Apoptosis by a Nonpolymorphic MHC Class II Peptide Proceeds by Activation of Protein Kinase C

Zang¹,

Kalache²,

Lin³

et al. 2005

Journal of the American Society of Nephrology

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Cross-Reactive Donor-Specific CD8+ Tregs Efficiently Prevent Transplant Rejection

et al. 2019

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Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection

et al. 2013

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Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection.Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo-and autoimmunity leading to allograft dysfunction.

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A Novel Mechanism for the Immunomodulatory Functions of Class II MHC–Derived Peptides

Cited by 8 publications

References 38 publications

MHC Class II–Mediated Apoptosis by a Nonpolymorphic MHC Class II Peptide Proceeds by Activation of Protein Kinase C

MHC Class II–Mediated Apoptosis by a Nonpolymorphic MHC Class II Peptide Proceeds by Activation of Protein Kinase C

Cross-Reactive Donor-Specific CD8+ Tregs Efficiently Prevent Transplant Rejection

Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection

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