Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals.

Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Research Abstract Details 

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Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Abstract Text:

Stanislaw M Stepkowski,Robert A Kirken,Barton W Trawick,Min Wang,Neelam Tejpal,Mou-Er Wang,Ling Tian,James Clark,Barry D Kahan,Stanislaw M Stepkowski,Robert A Kirken,Barton W Trawick,Min Wang,Neelam Tejpal,Mou-Er Wang,Ling Tian,James Clark,Barry D Kahan,

BACKGROUND: The various toxicities associated with the general immune suppression resulting from current clinical immunosuppressive therapies continue to plague transplant recipients as well as jeopardize allograft survival. METHODS: The present study utilized allochimeric class I MHC antigens (alpha1hu70-77-RT1.Aa) bearing only four donor RT1.Au polymorphic amino acids (a.a.; His70, Val73, Asn74, and Asn77) superimposed on the recipient RT1.Aa background to induce transplantation tolerance in the rat cardiac transplant model. RESULTS: Oral delivery of alpha1hu70-77-RT1.Aa protein alone (days 0-6) induced tolerance, as evidenced by inhibition of both acute and chronic rejection processes. Delivery of alpha1hu70-77-RT1.Aa with therapeutic doses of cyclosporine (CsA) also prevented chronic rejection, otherwise readily developed after treatment with CsA alone. A polymerase chain reaction (PCR)-based analysis showed that tolerant recipients had reduced numbers of interleukin (IL)-2/interferon (IFN)-gamma-producing T helper (Th)1 cells and elevated numbers of IL-4/IL-10-producing Th2 cells. Adoptive transfer experiments revealed that potent regulatory T cells mediated tolerance. The same T cells displayed diminished T cell receptor (TCR)-driven signaling via extracellular regulated kinase, AP-1, and NF-kappaB, as well as the common gamma-chain (gammac) cytokine-receptor-induced signaling by Janus kinase 3 (Jak3)/stimulators and activators of transcription Stat/5 pathways. Tolerance induction was prevented in vivo by inhibition of signal 2 by CTL4Ig or of signal 3 by either rapamycin, which disrupts the mammalian target of rapamycin, or AG490, which inhibits Jak3. Finally, partial or complete tyrosine phosphorylation of Zap70 was observed in alloantigen-specific T cell clones in response to tolerogenic versus immunogenic peptides, respectively. CONCLUSIONS: Tolerance induction by allochimeric proteins is achieved by partial TCR activation in the presence of signals 2 and 3, resulting in a skewed Th2 phenotype.

Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Publishing Authors By Initials

SM Stepkowski,RA Kirken,BW Trawick,M Wang,N Tejpal,ME Wang,L Tian,J Clark,BD Kahan,SM Stepkowski,RA Kirken,BW Trawick,M Wang,N Tejpal,ME Wang,L Tian,J Clark,BD Kahan,

For similar surgical procedures, operative: transplantation: transplantation, homologous research abstracts see: surgical procedures, operative: transplantation: transplantation, homologous research

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Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Transplantation

VOLUME: 73

Page Numbers: 1227-35

Journal Abbreviation: Transplantation

ISSN: 0041-1337

DAY: 27

MONTH: Apr

YEAR: 2002

Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Information

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LANGUAGE: eng

NlmUniqueID: 132144

Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Keywords Mesh Terms:

KEYWORDS: Transplantation, Homologous

MESH TERMS: immunology

Chemical & Substance for Abstract: Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals. Information

Substance Name: histocompatibility antigens RT, rat

Registry Number: 0

Grant and Affiliation Information for Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals.

AFFILIATION: Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. Stanislaw.Stepkowski@uth.tmc.edu

Country: United States

AGENCY: United States NHLBI

GRANT: HL 69723

ACRONYM: HL

MEDLINETA: Transplantation

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