Allochimeric Class I MHC Molecules Prevent Chronic Rejection and Attenuate Alloantibody Responses1

Singer, Jennifer S.; Mhoyan, Anna; Fishbein, Michael C.; Shen, Xiu-Da; Gao, Feng; Zhao, Danyun; Coito, Ana J.; Reemtsen, Brian; Amersi, Farin; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.; Ghobrial, Rafik M.

doi:10.1097/00007890-200110270-00014

Cited by 19 publications

(29 citation statements)

References 29 publications

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“…Visual inspection of the lists of gene downregulated by CsA 1 peptide treatment suggested the presence of genes related to immune response consistent with what is know about the possible mechanism of action of allochimeric peptide (Ghobrial et al, 1996;Semiletova et al, 2003Semiletova et al, , 2005Singer et al, 2001). Examination of the enrichment of gene ontologies (GO) provides a sta- UI-R-BJ0p-afu-c-02-0-UI.s1 UI-R-BJ0p Rattus norvegicus cDNA clone UI-R-BJ0p-afu-c-02-0-UI 3, mRNA sequence.…”

Section: Enrichment Of Gene Ontology Categories For Genes Downregulatsupporting

confidence: 72%

“…The subtherapeutic dose of CsA used in this study is not effective in preventing heart allograft rejection in rat model (Ghobrial et al, 1996;Semiletova et al, 2005;Singer et al, 2001). The same dose of CsA is, however, much more effective when administered in combination with the allochimeric peptide (Ghobrial et al, 1996;Semiletova et al, 2005, Singer et al, 2001.…”

Section: Gene Changes Associated With Csa and Csa 1 Peptide Treatmentmentioning

confidence: 63%

“…The same dose of CsA is, however, much more effective when administered in combination with the allochimeric peptide (Ghobrial et al, 1996;Semiletova et al, 2005, Singer et al, 2001. The lists of differentially expressed genes may provide some insight into the molecular mechanisms of action of these two immunosuppressants.…”

Section: Gene Changes Associated With Csa and Csa 1 Peptide Treatmentmentioning

confidence: 99%

“…It has been previously shown that major histocompatibility complex (MHC) class I allochimeric protein containing donor-type polymorphic epitopes displayed on recipient-type heavy chains administered in conjunction with subtherapeutic dose of cyclosporine (CsA) was able to induce indefinite survival of heterotopic cardiac allografts in rats (Ghobrial et al, 1996;Semiletova et al, 2003Semiletova et al, , 2005Singer et al, 2001 (Singer et al, 2001). Peri-or post-transplant administration of this molecule induced tolerance of WF heart allografts in ACI recipients (Semiletova et al, 2003(Semiletova et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

“…Such accommodation was evident by IgG and IgM vascular endothelial binding and marked reduction of DNA fragmentation (Semiletova et al, 2005). It has been also demonstrated that in vivo administration of modulated MHC class I proteins that express donor sequences within their a1 domains could immunomodulate the recipient's immune response (Ghobrial et al, 1996;Semiletova et al, 2003;Singer et al, 2001). The results of several studies suggest that the soluble MHC class I proteins exert the immunomodulating effect either by directly inhibiting T cell functions by receptor blockade (Hausman et al, 1993) or by inducing apoptosis of activated CD81 T cells (Zavazava and Kronke, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplantation model

Lisik

Gong

Tejpal

et al. 2009

Genesis

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The MHC class I allochimeric protein containing donor-type epitopes on recipient-type heavy chains induces indefinite survival of heterotopic cardiac allografts in rats. We analyzed gene expression profile of heart allograft tissue. Mutated peptide [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) immunogenic epitopes displayed on recipient-type (ACI, RT1a) was delivered into ACI recipients of WF hearts at the time of transplantation in addition to a 3 days course of oral cyclosporine. Microarray analysis was performed using Affymetrix Rat 230 2.0 Microarray. Allochimeric molecule treatment caused upregulation of genes involved in structural integrity of heart muscle, downregulation of IL-1beta a key modulator of the immune response, and downregulation of partitioning defective six homolog gamma PAR6, which is involved in T cell polarity, motility, and ability to scan dendritic cells (DC). These indicate that the immunosuppressive function of allochimeric molecule and/or the establishment of allograft tolerance depend on the induction of genes responsible for the heart tissue integrity, the suppression of cytokine pathway(s), and possibly the impairment of T cells mobility and their DC scanning ability. These novel findings may have important clinical implications for inhibition of chronic rejection in transplant recipients.

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Section: Enrichment Of Gene Ontology Categories For Genes Downregulatsupporting

confidence: 72%

Section: Gene Changes Associated With Csa and Csa 1 Peptide Treatmentmentioning

confidence: 63%

Section: Gene Changes Associated With Csa and Csa 1 Peptide Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplantation model

Lisik

Gong

Tejpal

et al. 2009

Genesis

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Rejection After Transplantation

Lipshutz¹,

Ascher²,

Roberts³

2005

Transplantation of the Liver

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Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

Semiletova

Shen

Feldman

et al. 2007

Cellular Immunology

Self Cite

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Functional topography of rat class I major histocompatibility complex (MHC) molecule was studied. The α 1 -helical sequences that are shared by class I RT1.Al and RT1.A u were substituted in the RT1.A a molecule to produce the composite [α 1h l/u ]-RT1.A a MHC class I allochimeric molecule. Dominant immunogenic epitopes that induce accelerated rejection were identified within the hypervariable regions of the α 1 domain of RT1.A a , RT1.A l , and RT1.A u . Peritransplant portal venous delivery of MHC class I allochimeric proteins, that included composite α 1 helical immunodominant epitopes of RT1.A u and RT1.A l , induced donor-specific tolerance to RT1 u (Wistar Furth, WF) and RT1 l Lewis, LEW) disparate cardiac allografts in ACI (RT1 a ) hosts. Allochimeric generated tolerance was characterized by absence of T cell deletion or anergy. Donor specific IgM allo-Abs was not detected, while IgG alloresponse was markedly attenuated in sera of tolerant hosts. Further, long-term allografts in allochimeric-conditioned hosts exhibited moderate B cell infiltration when compared to rejecting controls. Analysis of intragraft cytokines revealed selective upregulation of IL-10 and marked inhibition of IL-2, IFN-γ and IL-4. Our findings indicate the emergence of a peripherally induced tolerant state, afforded by the novel approach of soluble class I allochimeric conditioning that presents donor immunogenic epitopes in the context of recipient class I determinants.

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Allochimeric Class I MHC Molecules Prevent Chronic Rejection and Attenuate Alloantibody Responses1

Abstract: Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.

Cited by 19 publications

References 29 publications

Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplantation model

Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplantation model

Rejection After Transplantation

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

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