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Mohamed H. Sayegh - One of the best experts on this subject based on the ideXlab platform.

  • Physiological Mechanisms of RegulaTing AlloimmuniTy: CyTokines, CTLA-4, CD25+ Cells, and The AlloreacTive T Cell Clone Size
    Journal of immunology (Baltimore Md. : 1950), 2002
    Co-Authors: Masayuki Sho, Terry B Strom, Nader Najafian, Xin Xiao Zheng, Alan D Salama, Hiroshi Harada, Akira Yamada, Sigrid Sandner, Alberto Sánchez-fueyo, Mohamed H. Sayegh
    Abstract:

    The mechanisms underlying physiological regulaTion of alloimmune responses remain poorly defined. We invesTigaTed The roles of cyTokines, CTLA-4, CD25(+) T Cells, and apopTosis in regulaTing alloimmune responses in vivo. Two murine cardiac TransplanT models were used, B10.D2 (minor mismaTch) and C57BL/6 (major mismaTch), inTo BALB/c recipienTs. RecipienTs were wild Type, STAT4(-/-) (Th1 deficienT), or STAT6(-/-) (Th2 deficienT) mice. Minor mismaTched allografTs were accepTed sponTaneously in approximaTely 70% of wild Type and STAT4(-/-) mice. By conTrasT, There was significanTly shorTer grafT survival in minor mismaTched STAT6(-/-) mice. EiTher The adopTive Transfer of STAT4(-/-) splenocyTes or The adminisTraTion of IL-4Fc fusion proTein inTo STAT6(-/-) mice resulTed in long Term grafT survival. Blocking CTLA-4 signaling acceleraTed The rejecTion in all recipienTs, buT was more pronounced in The minor combinaTion. This was accompanied by an increased frequency of AlloreacTive T Cells. FurThermore, CTLA-4 blockade regulaTed CD4(+) or CD8(+) as well as Th1 or Th2 AlloreacTive T Cells. Finally, while anTi-CD25 TreaTmenT prolonged grafT survival in The major mismaTched combinaTion, The same TreaTmenT acceleraTed grafT rejecTion in The minor mismaTched group. The laTTer was associaTed wiTh an increased frequency of AlloreacTive T Cells and inhibiTion of T Cell apopTosis. These daTa demonsTraTe ThaT cyTokine regulaTion, CTLA-4 negaTive signaling, and T Cell apopTosis play criTical roles in regulaTing alloimmuniTy, especially under condiTions where The AlloreacTive T Cell clone size is relaTively small.

  • physiological mechanisms of regulaTing alloimmuniTy cyTokines cTla 4 cd25 Cells and The AlloreacTive T Cell clone size
    Journal of Immunology, 2002
    Co-Authors: Akira Yamada, Sigrid E Sandner, Terry B Strom, Nader Najafian, Alberto Sanchezfueyo, Xin Xiao Zheng, Alan D Salama, Mohamed H. Sayegh, Hiroshi Harada
    Abstract:

    The mechanisms underlying physiological regulaTion of alloimmune responses remain poorly defined. We invesTigaTed The roles of cyTokines, CTLA-4, CD25+ T Cells, and apopTosis in regulaTing alloimmune responses in vivo. Two murine cardiac TransplanT models were used, B10.D2 (minor mismaTch) and C57BL/6 (major mismaTch), inTo BALB/c recipienTs. RecipienTs were wild Type, STAT4−/− (Th1 deficienT), or STAT6−/− (Th2 deficienT) mice. Minor mismaTched allografTs were accepTed sponTaneously in ∼70% of wild Type and STAT4−/− mice. By conTrasT, There was significanTly shorTer grafT survival in minor mismaTched STAT6−/− mice. EiTher The adopTive Transfer of STAT4−/− splenocyTes or The adminisTraTion of IL-4Fc fusion proTein inTo STAT6−/− mice resulTed in long Term grafT survival. Blocking CTLA-4 signaling acceleraTed The rejecTion in all recipienTs, buT was more pronounced in The minor combinaTion. This was accompanied by an increased frequency of AlloreacTive T Cells. FurThermore, CTLA-4 blockade regulaTed CD4+ or CD8+ as well as Th1 or Th2 AlloreacTive T Cells. Finally, while anTi-CD25 TreaTmenT prolonged grafT survival in The major mismaTched combinaTion, The same TreaTmenT acceleraTed grafT rejecTion in The minor mismaTched group. The laTTer was associaTed wiTh an increased frequency of AlloreacTive T Cells and inhibiTion of T Cell apopTosis. These daTa demonsTraTe ThaT cyTokine regulaTion, CTLA-4 negaTive signaling, and T Cell apopTosis play criTical roles in regulaTing alloimmuniTy, especially under condiTions where The AlloreacTive T Cell clone size is relaTively small.

  • The cd154 cd40 T Cell cosTimulaTion paThway is required for hosT sensiTizaTion of cd8 T Cells by skin grafTs via direcT anTigen presenTaTion
    Journal of Immunology, 2002
    Co-Authors: Yuan Zhai, Alan D Salama, Mohamed H. Sayegh, Xiu Da Shen, Feng Gao, Ana J Coito, Barbara A Wasowska, Isabela Schmitt, Ronald W Busuttil, Jerzy W Kupiecweglinski
    Abstract:

    AlThough The CD154-CD40 T Cell cosTimulaTion paThway has been shown To mediaTe alloimmune responses in normal recipienTs, liTTle is known abouT iTs role in sensiTized hosTs. In This work, by using novel models of cardiac allografT rejecTion in skin-sensiTized CD154- and CD40-deficienT mice, we reaffirm The key role of CD154-CD40 signaling in hosT sensiTizaTion To alloanTigen in vivo. FirsT, we idenTified CD8 + T Cells as principal effecTors in execuTing acceleraTed rejecTion in our model. DisrupTion of CD154-CD40 signaling in recipienTs aT The T Cell side (CD154-deficienT) buT noT aT The APC side (CD40-deficienT) abrogaTed acceleraTed ( 100 days) grafT survival. This suggesTs ThaT The CD154-dependenT mechanism in hosT CD8 + T Cell sensiTizaTion operaTes via The direcT Ag presenTaTion. Then, in comparaTive sTudies of alloimmune responses in CD154-deficienT and wild-Type recipienTs, we showed ThaT, alThough AlloreacTive B Cell responses were inhibiTed, AlloreacTive T Cell responses were down-regulaTed selecTively in The CD8 + T Cell comparTmenT, leaving CD4 + T Cells largely unaffecTed. This unique alTeraTion in hosT alloreacTiviTy, seen noT only in peripheral lymphocyTes buT also in allografT infilTraTe, may represenT The key mechanism by which disrupTion of CD154-CD40 signaling prevenTs sensiTizaTion To alloanTigen in vivo and leads To long-Term allografT survival.

  • Th1 cyTokines programmed Cell deaTh and AlloreacTive T Cell clone size in TransplanT Tolerance
    Journal of Clinical Investigation, 2002
    Co-Authors: Koji Kishimoto, Sigrid E Sandner, Peter B Langmuir, Terry B Strom, Jaime Imitola, David M Rothstein, Laurence A Turka, Yongsheng Li, Mohamed H. Sayegh
    Abstract:

    The Th1 cyTokines IL-2 and IFN-gamma, which inhibiT T Cell proliferaTion and promoTe acTivaTion induced Cell deaTh, may be required To diminish AlloreacTive T Cell numbers and To fosTer Tolerance across full allogeneic barriers. However, we hypoThesized ThaT These cyTokines mighT be dispensable when The AlloreacTive T Cell clone size is relaTively small, as is seen in recipienTs of minor-mismaTched grafTs. We show ThaT AlloreacTive T Cell clone size of C57BL/6 mice againsT mulTiple minor-mismaTched 129X1/sv mice was approximaTely 4-9-fold smaller Than ThaT againsT MHC-mismaTched BALB/c mice. In The MHC-mismaTched combinaTion, CD28-B7 blockade by CTLA4Ig induced long-Term grafT survival in wild-Type recipienTs, buT This TreaTmenT was ineffecTive in IFNgamma(-/-) or IL-2(-/-) recipienTs. In conTrasT, in The minor-mismaTched combinaTion, CTLA4Ig induced long-Term allografT survival in wild-Type, IFNgamma(-/-), and IL-2(-/-) recipienTs. Bcl-x(L) Transgenic animals, which are defecTive in "passive" T Cell deaTh, are likewise sensiTive To The effecTs of CTLA4Ig only in The seTTing of The minor-mismaTch grafTs. Therefore, The AlloreacTive T Cell clone size is an imporTanT deTerminanT affecTing The need for Th1 cyTokines and T Cell deaTh in Tolerance inducTion. These daTa have implicaTions for The design of Tolerance sTraTegies in TransplanT recipienTs wiTh varying degrees of MHC mismaTching.

Peter S Heeger - One of the best experts on this subject based on the ideXlab platform.

  • AlloreacTive T Cell responses and acuTe rejecTion of single class ii mhc disparaTe hearT allografTs are under sTricT regulaTion by cd4 cd25 T Cells
    Journal of Immunology, 2005
    Co-Authors: Soren Schenk, Peter S Heeger, Sigrid Sandner, Danielle D Kish, Tarek Elsawy, Eise Chiffoleau, Chuangqui Chen, Anton V Gorbachev, Kiyotaka Fukamachi
    Abstract:

    Skin buT noT vascularized cardiac allografTs from B6.H-2bm12 mice are acuTely rejecTed by C57BL/6 recipienTs in response To The single class II MHC dispariTy. The underlying mechanisms prevenTing acuTe rejecTion of B6.H-2bm12 hearT allografTs by C57BL/6 recipienTs were invesTigaTed. B6.H-2bm12 hearT allografTs induced low levels of AlloreacTive effecTor T Cell priming in C57BL/6 recipienTs, and This priming was accompanied by low-level Cellular infilTraTion inTo The allografT ThaT quickly resolved. RecipienTs wiTh long-Term-surviving hearT allografTs were unable To rejecT B6.H-2bm12 skin allografTs, suggesTing poTenTial down-regulaTory mechanisms induced by The cardiac allografTs. DepleTion of CD25+ Cells from C57BL/6 recipienTs resulTed in 15-fold increases in AlloreacTive T Cell priming and in acuTe rejecTion of B6.H-2bm12 hearT grafTs. Similarly, reconsTiTuTion of B6.Rag−/− recipienTs wiTh wild-Type C57BL/6 splenocyTes resulTed in acuTe rejecTion of B6.H-2bm12 hearT grafTs only if CD25+ Cells were depleTed. These resulTs indicaTe ThaT acuTe rejecTion of single class II MHC-disparaTe B6.H-2bm12 hearT allografTs by C57BL/6 recipienTs is inhibiTed by The emergence of CD25+ regulaTory Cells ThaT resTricT The clonal expansion of AlloreacTive T Cells.

  • T Cell allorecogniTion and TransplanT rejecTion a summary and updaTe
    American Journal of Transplantation, 2003
    Co-Authors: Peter S Heeger
    Abstract:

    TransplanT biologisTs have made significanT progress over The lasT 20 years Towards unraveling The immunologic inTricacies of allografT rejecTion. This large body of work has resulTed in an improved undersTanding of T-Cell allorecogniTion aT a molecular level and has provided new insighT inTo The funcTional consequences resulTing from The allorecogniTion evenTs. The findings suggesT ThaT The survival and The hisTologic feaTures of a TransplanTed organ are influenced noT only by The T-Cell recogniTion paThway, buT also by The frequency, The induced effecTor funcTions and The specific Cellular TargeTs of The AlloreacTive T-Cell reperToire.

Robert L Fairchild - One of the best experts on this subject based on the ideXlab platform.

  • cxc chemokine ligand cxcl 9 and cxcl10 are anTagonisTic cosTimulaTion molecules during The priming of AlloreacTive T Cell effecTors
    Journal of Immunology, 2010
    Co-Authors: Danielle D Kish, Joshua M Rosenblum, Naohiko Shimoda, Austin D Schenk, Howard Zhang, Karen Keslar, Joshua M Farber, Robert L Fairchild
    Abstract:

    Donor Ag-reacTive CD4 and CD8 T Cell producTion of IFN-γ is a principal effecTor mechanism promoTing Tissue injury during allografT rejecTion. The CXCR3-binding chemokines CXCL9 and CXCL10 recruiT donor-reacTive T Cells To The allografT, buT Their role during The priming of donor-reacTive T Cells To effecTor funcTion is unknown. Using a murine model of MHC-mismaTched cardiac TransplanTaTion, we invesTigaTed The influence of CXCL9 and CXCL10 during donor-reacTive T Cell priming. In allografT recipienT spleens, CXCL9 and CXCL10 were expressed as early as 24 h posTTransplanT and increased wiTh similar kineTics, concurrenTly wiTh CXCR3 expression on T Cells. CXCL9, buT noT CXCL10, expression required NK Cell producTion of IFN-γ. The absence of CXCL9 in donor allografTs, recipienTs, or boTh significanTly decreased The frequency of donor-reacTive CD8 T Cells producing IFN-γ and increased The frequency of donor-reacTive CD8 T Cells producing IL-17A. In conTrasT, The absence of CXCL10 increased The frequency of IFN-γ–producing CD8 T Cells in a CXCL9-dependenT manner. These daTa provide novel evidence ThaT donor-reacTive CD8 T Cells use The CXCR3 chemokine axis as a cosTimulaTion paThway during priming To allografTs where CXCL9 promoTes The developmenT of IFN-γ–producing CD8 T Cells, and CXCL10 anTagonizes This skewing.

  • ccr5 is required for regulaTion of AlloreacTive T Cell responses To single class ii mhc mismaTched murine cardiac grafTs
    American Journal of Transplantation, 2009
    Co-Authors: T Nozaki, Joshua M Rosenblum, Austin D Schenk, Robert L Fairchild, Daisuke Ishii
    Abstract:

    The effecTor CD4 T-Cell response in wild-Type C57BL/6 recipienTs of single class II MHC-disparaTe B6.H-2bm12 cardiac allografTs is resTricTed by CD4+CD25+ regulaTory T Cells (Tregs) resulTing in long-Term allografT survival. To invesTigaTe The role chemokine recepTors mighT play in Treg funcTion, This sTudy TesTed The requiremenT for CCR5 on Tregs To suppress The alloimmune response in C57BL/6 recipienTs of B6.H-2bm12 cardiac allografTs. In conTrasT To The long-Term survival of B6.H-2bm12 allografTs in wild-Type recipienTs (>100 days), The allografTs were acuTely rejecTed wiThin 25 days in CCR5−/− recipienTs wiTh inTense infilTraTion of CD4 T Cells. Numbers and duraTion of donor-reacTive CD4 T Cells producing IFN-γ and IL-4 were markedly increased in spleens of B6.CCR5−/− versus wild-Type recipienTs. Wild-Type and B6.CCR5−/− mice had equivalenT numbers of splenic FoxP3+ Tregs before and following TransplanTaTion, and These Tregs were equivalenTly suppressive in viTro. However, diminished numbers of FoxP3+ Tregs infilTraTed B6.H-2bm12 allografTs in B6.CCR5−/− recipienTs. AdopTive Transfer of wild-Type, buT noT CCR5-deficienT, CD4+CD25+ Tregs To CCR5−/− recipienTs resTored long-Term survival of B6.H-2bm12 cardiac grafTs. CollecTively, These resulTs indicaTe ThaT CCR5 expression is required for The regulaTory funcTions of Tregs ThaT resTricT AlloreacTive CD4 T-Cell responses To single class II MHC-mismaTched cardiac allografTs.

An Billiau - One of the best experts on this subject based on the ideXlab platform.

  • human mulTipoTenT adulT progeniTor Cells are nonimmunogenic and exerT poTenT immunomodulaTory effecTs on AlloreacTive T Cell responses
    Cell Transplantation, 2013
    Co-Authors: Sandra Jacobs, Jef Pinxteren, Valerie D Roobrouck, Ariane Luyckx, Wouter Vant Hof, Robert J Deans, Catherine M Verfaillie, Mark Waer, An Billiau, Stefaan Van Gool
    Abstract:

    MulTipoTenT adulT progeniTor Cells (MAPCs) are bone marrow-derived nonhemaTopoieTic sTem Cells wiTh a broad differenTiaTion poTenTial and exTensive expansion capaciTy. A comparaTive sTudy beTween h...

  • g csf sTem Cell mobilizaTion in human donors induces polymorphonuclear and mononuclear myeloid derived suppressor Cells
    Clinical Immunology, 2012
    Co-Authors: Ariane Luyckx, Mark Waer, Elio Schouppe, Omer Rutgeerts, Caroline Lenaerts, Sabine Fevery, Timothy Devos, Daan Dierickx, Jo A Van Ginderachter, An Billiau
    Abstract:

    AbsTracT The role of myeloid-derived suppressor Cells (MDSC) is emerging in TransplanTaTion. An expansion of myeloid progeniTor Cells wiTh suppressive capaciTy has been reporTed To occur as a bysTander phenomenon in The course of allogeneic hemaTopoieTic sTem Cell TransplanTaTion (allo-HSCT) proTocols, parTicularly, in mice during bone marrow chimerism inducTion and in human sTem Cell donors during G-CSF-mobilizaTion proTocols. HypoThesizing ThaT such ‘regulaTory myeloid Cells’ play a role in regulaTing posT-TransplanT T-Cell alloreacTiviTy, we performed a phenoTypical and funcTional characTerizaTion of These Cells in peripheral blood sTem Cell grafTs of G-CSF-TreaTed donors. We demonsTraTe ThaT expanding myeloid Cells in The peripheral blood of G-CSF-mobilized donors comprise The Typical phenoType of The mononuclear and polymorphonuclear MDSC-subTypes ThaT were recenTly described in cancer paTienTs, and ThaT boTh MDSC-subseTs have The capaciTy To regulaTe AlloreacTive T-Cell responses in-viTro. This sTudy provides The basis for invesTigaTing The clinical relevance of MDSC and MDSC-subTypes in human allo-HSCT.

  • ocT4 negaTive mulTipoTenT adulT progeniTor Cells and mesenchymal sTem Cells as regulaTors of T Cell alloreacTiviTy in mice
    Immunology Letters, 2011
    Co-Authors: Ariane Luyckx, Sandra Jacobs, Valerie D Roobrouck, Catherine M Verfaillie, Mark Waer, Stefaan Van Gool, Omer Rutgeerts, Caroline Lenaerts, Lien De Somer, An Billiau
    Abstract:

    MulTipoTenT adulT progeniTor Cells (MAPC) are clinically being explored as an alTernaTive To mesenchymal sTem Cells (MSC) for The immunomodulaTory conTrol of grafT-versus-hosT disease (GvHD). Here, we performed an exploraTive sTudy of The immunomodulaTory poTenTial of mouse MAPC (mMAPC), in comparison wiTh ThaT of MSC (mMSC) using experimenTal models of T-Cell alloreacTiviTy. Suppressive effecTs of OcT4-expressing mMAPC have been described previously; here, we sTudied mMAPC expressing low To no OcT4 ('mClone-3'), recenTly shown To be mosT represenTaTive for The human MAPC counTerparT. mClone-3 and mMSC exhibiTed similar immunophenoType and in viTro immunogenic behavior. Allogeneic T-Cell↔dendriTic Cell-proliferaTion assays showed sTrong dose-dependenT T-Cell-suppressive effecTs of boTh mClone-3 and mMSC. In a popliTeal lymph node assay, mClone-3 and mMSC equally suppressed in vivo AlloreacTive T-Cell expansion. We conclude ThaT mouse MAPC and MSC exhibiT similar immunosuppressive behavior in in viTro and local in vivo GvHD assays.

Joshua M Rosenblum - One of the best experts on this subject based on the ideXlab platform.

  • cxc chemokine ligand cxcl 9 and cxcl10 are anTagonisTic cosTimulaTion molecules during The priming of AlloreacTive T Cell effecTors
    Journal of Immunology, 2010
    Co-Authors: Danielle D Kish, Joshua M Rosenblum, Naohiko Shimoda, Austin D Schenk, Howard Zhang, Karen Keslar, Joshua M Farber, Robert L Fairchild
    Abstract:

    Donor Ag-reacTive CD4 and CD8 T Cell producTion of IFN-γ is a principal effecTor mechanism promoTing Tissue injury during allografT rejecTion. The CXCR3-binding chemokines CXCL9 and CXCL10 recruiT donor-reacTive T Cells To The allografT, buT Their role during The priming of donor-reacTive T Cells To effecTor funcTion is unknown. Using a murine model of MHC-mismaTched cardiac TransplanTaTion, we invesTigaTed The influence of CXCL9 and CXCL10 during donor-reacTive T Cell priming. In allografT recipienT spleens, CXCL9 and CXCL10 were expressed as early as 24 h posTTransplanT and increased wiTh similar kineTics, concurrenTly wiTh CXCR3 expression on T Cells. CXCL9, buT noT CXCL10, expression required NK Cell producTion of IFN-γ. The absence of CXCL9 in donor allografTs, recipienTs, or boTh significanTly decreased The frequency of donor-reacTive CD8 T Cells producing IFN-γ and increased The frequency of donor-reacTive CD8 T Cells producing IL-17A. In conTrasT, The absence of CXCL10 increased The frequency of IFN-γ–producing CD8 T Cells in a CXCL9-dependenT manner. These daTa provide novel evidence ThaT donor-reacTive CD8 T Cells use The CXCR3 chemokine axis as a cosTimulaTion paThway during priming To allografTs where CXCL9 promoTes The developmenT of IFN-γ–producing CD8 T Cells, and CXCL10 anTagonizes This skewing.

  • ccr5 is required for regulaTion of AlloreacTive T Cell responses To single class ii mhc mismaTched murine cardiac grafTs
    American Journal of Transplantation, 2009
    Co-Authors: T Nozaki, Joshua M Rosenblum, Austin D Schenk, Robert L Fairchild, Daisuke Ishii
    Abstract:

    The effecTor CD4 T-Cell response in wild-Type C57BL/6 recipienTs of single class II MHC-disparaTe B6.H-2bm12 cardiac allografTs is resTricTed by CD4+CD25+ regulaTory T Cells (Tregs) resulTing in long-Term allografT survival. To invesTigaTe The role chemokine recepTors mighT play in Treg funcTion, This sTudy TesTed The requiremenT for CCR5 on Tregs To suppress The alloimmune response in C57BL/6 recipienTs of B6.H-2bm12 cardiac allografTs. In conTrasT To The long-Term survival of B6.H-2bm12 allografTs in wild-Type recipienTs (>100 days), The allografTs were acuTely rejecTed wiThin 25 days in CCR5−/− recipienTs wiTh inTense infilTraTion of CD4 T Cells. Numbers and duraTion of donor-reacTive CD4 T Cells producing IFN-γ and IL-4 were markedly increased in spleens of B6.CCR5−/− versus wild-Type recipienTs. Wild-Type and B6.CCR5−/− mice had equivalenT numbers of splenic FoxP3+ Tregs before and following TransplanTaTion, and These Tregs were equivalenTly suppressive in viTro. However, diminished numbers of FoxP3+ Tregs infilTraTed B6.H-2bm12 allografTs in B6.CCR5−/− recipienTs. AdopTive Transfer of wild-Type, buT noT CCR5-deficienT, CD4+CD25+ Tregs To CCR5−/− recipienTs resTored long-Term survival of B6.H-2bm12 cardiac grafTs. CollecTively, These resulTs indicaTe ThaT CCR5 expression is required for The regulaTory funcTions of Tregs ThaT resTricT AlloreacTive CD4 T-Cell responses To single class II MHC-mismaTched cardiac allografTs.