The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

Kishimoto, Kenji; Dong, Victor; Issazadeh, Shohreh; Fedoseyeva, Eugenia V.; Waaga, Ana Maria; Yamada, Akira; Sho, Masayuki; Bénichou, Gilles; Auchincloss, Hugh; Grusby, Michael J.; Khoury, Samia J.; Sayegh, Mohamed H.

doi:10.1172/jci9586

Cited by 127 publications

(95 citation statements)

References 60 publications

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“…Interestingly, like anti-CD45RB, donor-specific transfusion synergizes with anti-CD40L therapy in murine transplant models, and also promotes strong Th2 deviation (10,35). Indeed, recent data from our group using STAT4 and STAT6 (important in Th1 and Th2 differentiation, respectively) knockout mice show that CD40L blockade was less effective in a predominantly Th1 environment (STAT6 knockout) unless combined with donor splenocytes (62). Whether inhibition of Th1 cytokines by combined anti-CD45RB and anti-CD40L is caused by decreased infiltration by APCs and CD8 cells or vice versa is not clear.…”

Section: Discussionmentioning

confidence: 98%

Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models

Rothstein

Livak

Kishimoto

et al. 2001

The Journal of Immunology

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The induction and maintenance of allograft tolerance is a daunting challenge. Although combined blockade of CD28 and CD40 ligand (CD40L)-costimulatory pathways prevents allograft rejection in some murine models, this strategy is unable to sustain engraftment in the most immunogenic allograft and strain combinations. By targeting T cell activation signals 1 and 2 with the novel combination of anti-CD45RB and anti-CD40L, we now demonstrate potent enhancement of engraftment in C57BL/6 recipients that are relatively resistant to costimulatory blockade. This combination significantly augments the induction of tolerance to islet allografts and dramatically prolongs primary skin allograft survival. Compared with either agent alone, anti-CD45RB plus anti-CD40L inhibits periislet infiltration by CD8 cells, B cells, and monocytes; inhibits Th1 cytokines; and increases Th2 cytokine expression within the graft. These data indicate that interference with activation signals one and two may provide synergy essential for prolonged engraftment in situations where costimulatory blockade is only partially effective.

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Section: Discussionmentioning

confidence: 98%

Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models

Rothstein

Livak

Kishimoto

et al. 2001

The Journal of Immunology

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“…ELISPOT assays were performed as described previously (16,18,19). Immunospot plates (Cellular Technology, Cleveland, OH) were coated with 4 g/ml rat anti-mouse IFN capture mAb (R4-6A2), then blocked for 1 h with sterile PBS that contained 1% BSA.…”

Section: Elispotmentioning

confidence: 99%

Mechanism of Action of Donor-Specific Transfusion in Inducing Tolerance

Kishimoto¹,

Yuan²,

Auchincloss³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Donor-specific transfusion (DST) can synergize with T cell co-stimulatory blockade in inducing tolerance in several transplant models, but the mechanism of action of DST is poorly characterized. This study used genetically altered mice in an established model of cardiac transplantation to study the role of MHC and co-stimulatory molecule expression on DST cells in mediating the immunomodulatory effects of DST. In addition, to examine the role of indirect antigen presentation in the effect of DST, experiments used recipient mice that do not express MHC class II molecules on peripheral antigen-presenting cells, but do have functional CD4 ϩ T cells (II Ϫ 4 ϩ ). As previously reported, treatment with DST from wild-type donors in combination with CD154 blockade induced tolerance in wild-type recipients of cardiac allografts. Tolerance in this model is also induced despite the absence of MHC class I and II, CD40, or B7 molecules on transfused cells. In contrast, eliminating the indirect pathway using II Ϫ 4 ϩ recipients blocked the induction of long-term cardiac allograft survival by DST. These results indicate that the indirect antigen recognition pathway mediates the immunomodulatory effect of DST in inducing transplantation tolerance in vivo.Numerous studies have shown that transfusion of allogeneic donor cells (donor-specific transfusion [DST]) has the potential to induce tolerance to a specific allograft. In particular, transfusion of donor splenic leukocytes at the time of transplantation synergizes with B7/CD154 co-stimulatory signal blockade in promoting long-term allograft survival, inducing tolerance, and preventing chronic allograft rejection in some models (1-4). Postulated mechanisms of the immunomodulatory functions of DST include clonal deletion (5,6), induction of anergy (7), generation of regulatory cells (8,9), regulation of cytokine production (5,7,10), promotion of microchimerism (10), provision of soluble MHC antigens (11), or a combination of these mechanisms (5,7,10,12). However, the proximal mechanisms involving alloreactive T cell interactions with DST remain unknown. The aim of this study was to investigate the role of MHC and co-stimulatory molecule expression on the immunomodulatory functions of DST in a fully allogeneic cardiac transplant model using specific gene knockout mice as sources of DST. In addition, to investigate the role of indirect recognition of antigen provided by DST, we used as recipient transgenic mice that express MHC class II only on thymic epithelium and develop normal numbers of CD4 ϩ T cells but express no MHC class II on peripheral antigen-presenting cells (APC) (13).

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“…In several models, CD28-B7 blockade alone or in combination with donor-specific transfusion (DST), 3 has been shown to prevent acute rejection, induce longterm allograft survival (1)(2)(3)(4), and prevent the development and progression of chronic rejection (5,6). However, the same degree of efficacy is not seen when more stringent transplantation models have been used (7)(8)(9)(10).…”

Section: T Is Now Firmly Established That Costimulatory Signals Prmentioning

confidence: 99%

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

Yuan

Salama

Dong

et al. 2003

The Journal of Immunology

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The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloimmune response remains unexplored. Furthermore, its interactions with other costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-γ-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 ± 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 ± 2.8 days) as did CTLA4Ig (MST: 21.5 ± 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 ± 12.7 days) and prevented the expansion and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloimmune responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.

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The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

Cited by 127 publications

References 60 publications

Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models

Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models

Mechanism of Action of Donor-Specific Transfusion in Inducing Tolerance

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

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