Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination

Zavazava, Nicholas; Fändrich, F.; Zhu, Xiaofeng; Freese, A.; Behrens, Dirk; Yoo-Ott, Kyoung-Ae

doi:10.1002/jlb.67.6.793

Cited by 33 publications

(15 citation statements)

References 30 publications

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“…[9][10][11] In other studies, class I-and class II-derived allopeptides were used to induce tolerance. [12][13][14] By studying a series of rat-derived synthetic allo-MHC peptides, immunodominant regions of allogeneic MHC molecules that modulate graft survival were identified. 13 These studies revealed that some regions of MHC class I molecules are not immunogenic and do not modulate alloresponses.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] By studying a series of rat-derived synthetic allo-MHC peptides, immunodominant regions of allogeneic MHC molecules that modulate graft survival were identified. 13 These studies revealed that some regions of MHC class I molecules are not immunogenic and do not modulate alloresponses. Thus, immunodominant peptides are defined here as peptides derived from an allo-MHC molecule and capable of inducing alloresponses.…”

Section: Introductionmentioning

confidence: 99%

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HLA-B7 β-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses

Freese

Zavazava

2002

Blood

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Chronic rejection of transplanted allografts is the major cause of graft loss after clinical solid organ transplantation. Recent data link the indirect presentation of allopeptides to chronic graft loss; thus, identification of immunodominant epitopes on major histocompatibility complex (MHC) antigens could significantly contribute to establishing novel ways for monitoring and managing chronic rejection. Here, we show that synthetic allo-MHC-derived peptides covering the polymorphic region 56 to120 of HLA-B7 modulate alloresponses. In particular, the 2 ␤-pleated sheet-derived peptides covering residues 91 to 105 and 96 to 120, respectively, but not sequences from the ␣1 helix, were presented by autologous peripheral blood lymphocytes to induce T-cell proliferation. In addition, the 2 ␤-pleated sheetderived peptides and the ␣1-derived peptide residues 60 to 75 abrogated lysis of HLA-B7 target cells by anti-HLA-B7 cytotoxic T lymphocytes (CTLs). Although most residues between 91 and 120 are normally not directly accessible to T cells, our results indicate that peptides derived from the lower surface of the peptidebinding groove of HLA-B7 are immunodominant in HLA-B7 alloresponses. To characterize the binding and stability of allopeptides to T cells, the 62-70 peptidederived from the 60-75 allopeptide that blocked cytotoxicity of anti-HLA-B7 CTL-was synthesized and coupled with fluorescein isothiocyanate. The peptide specifically labeled anti-B7 CTL, but not anti-HLA-A2 CTL as measured by flow cytometry. Peptide binding to CTL was specific at 4°C and remained stable for 12 hours, whereas it remained stable for less than 2 hours at 37°C. These studies allow the identification of HLA-B7 T-cell epitopes and reveal for the first time a novel, previously unrecognized application of synthetic HLA-derived allopeptides to visualize alloreactive T cells. IntroductionStructural studies show that T-cell receptor (TCR) contacts bind peptide and large stretches of ␣1 and ␣2 major histocompatibility complex (MHC) helices. 1,2 In general, endogenous peptides derived from allo-MHC are seen by T cells as foreign-eliciting alloresponses. 3 T cells may recognize peptide-induced conformational changes, and they may also recognize surface MHC structures in addition to or independent of bound peptide. 4 Furthermore, allospecific cytotoxic T lymphocytes (CTLs) that are peptidedependent and peptide-specific have been described in the literature. 5 In general, however, when donor and recipient MHCs are structurally similar, the endogenous peptide appears to be the dominant target of alloreactive T cells, 5-7 a phenomenon backed by clinical data in graft-versus-host disease. 8 Synthetic allopeptides have been used in many different models to modulate alloresponses and to study alloreactivity. [9][10][11] In other studies, class I-and class II-derived allopeptides were used to induce tolerance. 12-14 By studying a series of rat-derived synthetic allo-MHC peptides, immunodominant regions of allogeneic MHC molecules that modulate graft surviv...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HLA-B7 β-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses

Freese

Zavazava

2002

Blood

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“…Oral application of antigen is able to induce antigen-specific peripheral tolerance (42) and is a promising approach for the treatment of autoimmune diseases or allograft rejection (3,16,26,34,44,46,48).…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon is known as oral tolerance (17). In recent years, various experimental models exploiting oral tolerance showed its potential in prevention and treatment of diseases such as encephalomyelitis, arthritis, uveitis, myasthenia gravis, type 1 diabetes, and allograft rejection (3,16,26,34,44,46,48). However, translation of oral tolerance into clinical studies proved to be difficult (7,14,24,33,39,43).…”

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confidence: 99%

Oral gene application using chitosan-DNA nanoparticles induces transferable tolerance

Heim¹,

Goldmann²,

Spriewald³

et al. 2013

Thorac cardiovasc Surg

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Oral tolerance is a promising approach to induce unresponsiveness to various antigens. The development of tolerogenic vaccines could be exploited in modulating the immune response in autoimmune disease and allograft rejection. In this study, we investigated a nonviral gene transfer strategy for inducing oral tolerance via antigen-encoding chitosan-DNA nanoparticles (NP). Oral application of ovalbumin (OVA)-encoding chitosan-DNA NP (OVA-NP) suppressed the OVA-specific delayed-type hypersensitivity (DTH) response and anti-OVA antibody formation, as well as spleen cell proliferation following OVA stimulation. Cytokine expression patterns following OVA stimulation in vitro showed a shift from a Th1 toward a Th2/Th3 response. The OVA-NP-induced tolerance was transferable from donor to naïve recipient mice via adoptive spleen cell transfer and was mediated by CD4 ؉ CD25 ؉ T cells. These findings indicate that nonviral oral gene transfer can induce regulatory T cells for antigen-specific immune modulation.

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“…The question is how do we surmount chronic rejection? It has been shown that targeting donor MHC peptides to dendritic cells [12] or administering them either intrathymically [13], orally [14], or as donor peptide-pulsed recipient APCs [15] induces tolerance through the indirect pathway of allorecognition. Could MHC-Ig dimers -being chimeric molecules containing donor MHC molecules -act in similar fashion?…”

Section: Fig 2: Secretion Of Mhc-ig Dimersmentioning

confidence: 99%

MHC-Ig Dimers: The next Frontier in Transplantation Immunology

Wigina

Jeza

2015

Int Jour of Biomed Res

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Organ transplantation offers hope to a variety of patients with terminal functioning organs and tissues. This is currently made possible by administration of general immunosuppressive drugs. To date, inducing tolerance to allografts has become the holy grail of every transplantation immunologist. In effect, there has been a great deal of research aiming to come up with alternative therapeutic mechanisms that would allow one to do away with or reduce the amount of general immunosuppressive drugs used either at the induction, maintenance, or both phases. It has been shown in recent years that MHC-Ig dimers can induce suppression of alloresponsive T cells in a donor specific fashion. Consequently, MHC-Ig fusion proteins are currently forming the next field for exploitation which is great progress in transplantation immunology since the discovery of the first immunosuppressive drugs in terms of inducing tolerance to transplanted organs and tissues. This review aims to discuss this progress.

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Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination

Cited by 33 publications

References 30 publications

HLA-B7 β-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses

HLA-B7 β-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses

Oral gene application using chitosan-DNA nanoparticles induces transferable tolerance

MHC-Ig Dimers: The next Frontier in Transplantation Immunology

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