Different Mechanisms of Cardiac Allograft Rejection in Wildtype and CD28-deficient Mice

Szot, Gregory L.; Zhou, Ping; Rulifson, Ingrid C.; Wang, Jun; Guo, Zhong; Kim, Oliver; Newell, Kenneth A.; Thistlethwaite, J. Richard; Bluestone, Jeffrey A.; Alegre, Maria‐Luisa

doi:10.1034/j.1600-6143.2001.010108.x

Cited by 50 publications

(50 citation statements)

References 46 publications

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“…As previously described, CD4 Ϫ/Ϫ mice spontaneously accepted B/c heart allografts (31). LM infection resulted in acute rejection in 60% of CD4 Ϫ/Ϫ recipients of cardiac allografts (Fig.…”

Section: Cd4 ϩ or Cd8 ϩ T Cells Can Mediate Allograft Rejection In Lmmentioning

confidence: 52%

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Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Wang¹,

Chen

Ahmed³

et al. 2008

The Journal of Immunology

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101

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Exposure to certain viruses and parasites has been shown to prevent the induction of transplantation tolerance in mice via the generation of cross-reactive memory T cell responses or the induction of bystander activation. Bacterial infections are common in the perioperative period of solid organ allograft recipients in the clinic, and correlations between bacterial infections and acute allograft rejection have been reported. However, whether bacterial infections at the time of transplantation have any effect on the generation of transplantation tolerance remains to be established. We used the Gram-positive intracellular bacterium Listeria monocytogenes (LM) as a model pathogen because its effects on immune responses are well described. Perioperative LM infection prevented cardiac and skin allograft acceptance induced by anti-CD154 and donor-specific transfusion in mice. LM-mediated rejection was not due to the generation of cross-reactive T cells and was largely independent of signaling via MyD88, an adaptor for most TLRs, IL-1, and IL-18. Instead, transplant rejection following LM infection was dependent on the expression of the phagosome-lysing pore former listeriolysin O and on type I IFN receptor signaling. Our results indicate that bacterial exposure at the time of transplantation can antagonize tolerogenic regimens by enhancing alloantigen-specific immune responses independently of the generation of cross-reactive memory T cells.

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Section: Cd4 ϩ or Cd8 ϩ T Cells Can Mediate Allograft Rejection In Lmmentioning

confidence: 52%

“…Cryostat sections were stained with anti-CD4, anti-CD8, anti-IgG, and anti-IgM Abs as previously described (31).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Wang¹,

Chen

Ahmed³

et al. 2008

The Journal of Immunology

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101

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“…Perhaps most importantly, the clinical experience with these therapies has not lived up to expectations based on preclinical tests. The basis for the most recent failures remains unclear, however increasing evidence suggests that CD8-mediated T-cell responses may be uniquely CD28/CD154 independent (36,38,(62)(63)(64)(65)(66). In the present study, we considered a different hypothesis, namely that there might be a different role for these costimulatory pathways in direct vs. indirect antigen presentation.…”

Section: Discussionmentioning

confidence: 99%

“…In most instances where costimulatory blockade fails to induce tolerance, CD8π T cells play a critical role in the graft rejection. This includes the rejection of allogeneic hearts by CD28-deficient mice and CD28-independent intestinal allograft rejection (36,38). In fact, there is a correlation between the ability of CD28 and CD154 antagonists to block skin allograft rejection and the prominence of CD8π T cells in the rejection process in certain strain combinations (39).…”

Section: Introductionmentioning

confidence: 99%

Inability to Induce Tolerance Through Direct Antigen Presentation

Rulifson

Szot

Palmer

et al. 2002

American Journal of Transplantation

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Both the direct and indirect antigen presentation pathways are important mechanisms for T cell-mediated allograft rejection. Studies using knockout mice and monoclonal antibodies have demonstrated that CD4π T cells are both necessary and sufficient for the rejection of allogeneic tissues, including skin, heart, and islet. Furthermore, combined blockade of the CD28/B7 and CD154/CD40 costimulatory pathways induces tolerance in multiple CD4π T-cell dependent allograft models. In this study, we addressed the T-cell requirement for costimulation in direct antigen presentation. We demonstrated that class II-specific alloreactive Tcell receptor transgenic T cells were sufficient to mediate allograft rejection independent of costimulatory blockade. Analysis of the costimulatory capacity of different antigen presenting cell (APC) populations demonstrated that APCs resident within the donor skin, Langerhans cells, are potent stimulators not requiring CD28-or CD154-dependent costimulation for direct major histocompatibility complex (MHC) antigen presentation. These results complement previous work examining the role of costimulation on CD8π T cells, supporting a model in which the effectiveness of costimulatory blockade in the setting of transplantation may be selective for the indirect pathway of MHC alloantigen presentation.

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“…In this experiment, 2 ϫ 10 7 splenocytes from II Ϫ 4 ϩ mice were transferred to WT B6 recipients of Balb/c allografts to increase the frequency of directly alloreactive T cells in WT animals. The number of T cells used is based on published studies indicating that numbers smaller than what we used, when transferred into nude recipients, can mediate acute allograft rejection (23). Despite the presence of additional CD4 T cells from II Ϫ 4 ϩ mice, MR1 ϩ DST induced long-term survival in three of four mice (Ͼ60 d).…”

Section: Long-term Cardiac Allograft Survival Is Not Achieved In II ϫmentioning

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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Different Mechanisms of Cardiac Allograft Rejection in Wildtype and CD28-deficient Mice

Cited by 50 publications

References 46 publications

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Inability to Induce Tolerance Through Direct Antigen Presentation

Mechanism of Action of Donor-Specific Transfusion in Inducing Tolerance

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