Prevention of T-cell activation by rhCTLA4-Ig and anti-CD40L monoclonal antibody results in indefinite islet allograft survival

Rastellini, Cristiana; Salam, Abdus; Kuddus, Ruhul; Aı̈touche, Abdelouahab; Субботин, Владимир; Braun, M; Leach, Richard J.; Peach, Robert; Fung, John J.; Starzl, Thomas E.; Rao, Abdul S.

doi:10.1016/s0041-1345(98)01979-4

Cited by 12 publications

(11 citation statements)

References 4 publications

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“…Our results differ from previous studies in which MR1 monotherapy was insufficient to prevent islet allograft rejection in mice (18,32). However, the dosage and timing of therapy used in these studies were different, and these parameters seem to be critical for the success of treatment (10,20,33,34).…”

Section: Rd Molano and Associatescontrasting

confidence: 99%

Prolonged Islet Graft Survival in NOD Mice by Blockade of the CD40-CD154 Pathway of T-Cell Costimulation

Molano

Berney

et al. 2001

Diabetes

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Allorejection and recurrence of autoimmunity are the major barriers to transplantation of islets of Langerhans for the cure of type 1 diabetes in humans. CD40-CD154 (CD40 ligand) interaction blockade by the use of anti-CD154 monoclonal antibody (mAb) has shown efficacy in preventing allorejection in several models of organ and cell transplantation. Here we report the beneficial effect of the chronic administration of a hamster anti-murine CD154 mAb, MR1, in prolonging islet graft survival in NOD mice. We explored the transplantation of C57BL/6 islets into spontaneously diabetic NOD mice, a combination in which both allogeneic and autoimmune components are implicated in graft loss. Recipients were treated either with an irrelevant control antibody or with MR1. MR1 administration was effective in prolonging allograft survival, but did not provide permanent protection from diabetes recurrence. The autoimmune component of graft loss was studied in spontaneously diabetic NOD mice that received syngeneic islets from young male NOD mice. In this combination, a less dramatic yet substantial delay in diabetes recurrence was observed in the MR1-treated recipients when compared with the control group. Finally, the allogeneic component was explored by transplanting C57BL/6 islets into chemically induced diabetic male NOD mice. In this setting, long-term graft survival (>100 days) was achieved in MR1-treated mice, whereas control recipients rejected their grafts within 25 days. In conclusion, chronic blockade of CD154 results in permanent protection from allorejection and significantly delays recurrence of diabetes in NOD mice.

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Section: Rd Molano and Associatescontrasting

confidence: 99%

Prolonged Islet Graft Survival in NOD Mice by Blockade of the CD40-CD154 Pathway of T-Cell Costimulation

Molano

Berney

et al. 2001

Diabetes

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“…Novel immunotherapeutic reagents, such as CTLA4Ig or anti-CD154, have been extremely effective in specifically blocking T-cell responses in vitro (24)(25)(26) and inducing long-term survival of organ and tissue allografts (33,35,(58)(59)(60). Notably, studies by Larsen and colleagues provided compelling evidence for the importance of CD28/ B7 and CD154/CD40 in CD4π T-cell-mediated skin allograft rejection (24,37).…”

Section: Discussionmentioning

confidence: 99%

“…B6 aBM12 TCR Tg mice were grafted with BM12 skin or BM12 skin deficient for B7-1 and B7-2 (BM12.B7-/-). Figure 5 illustrates a comparison of graft rejection between normal BM12 skin ( , MSTΩ 11.7 days, SE Ω 0.28) and skin (24,33,35,(58)(59)(60), combined blockade of CD28/B7 and CD154/CD40 interactions failed to prevent rejection in this system. Thus, although costimulation may play a role in the rejection process, the data suggest that it is not essential for mediating rejection.…”

Section: Direct Class II Antigen Presentation and Tolerancementioning

confidence: 99%

“…Numerous studies also indicated that the CD28/B7 and CD154/CD40 costimulatory pathways were critical regulators of allograft rejection (24,25,(27)(28)(29)(30)(31)(32)(33)(34)(35), Direct Class II Antigen Presentation and Tolerance specifically in CD4π T-cell-mediated rejection (36,37). Recent studies point to a differential role of CD28/B7 and CD154/CD40 costimulation in CD4 vs. CD8 T-cell-mediated allogeneic responses.…”

Section: Introductionmentioning

confidence: 99%

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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 both EAE and Theiler's virus-induced demyelinating disease models of MS [176,221,222] and lupus nephritis [198,201], treatment during ongoing disease has led to significant beneficial effects. In addition, CD154 blockade has been demonstrated to delay transplant rejection [236][237][238][239][240][241][242][243] and prevent destructive activation of allogeneic bone marrow transplant [244][245][246]. CD154 blockade has also been shown to effectively allow graft acceptance in islet transplant treatment of diabetic animals [226,237,239,240,247,248].…”

Section: Blocking Cd40 Engagement On Apcs (Anti-cd154 Blockade)mentioning

confidence: 99%

Therapeutic Blockade of TCR Signal Transduction and Co-Stimulation in Autoimmune Disease

Howard

Kohm²,

Castaneda

et al. 2005

CDTIA

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Autoimmune diseases are initiated and maintained by presentation of self antigen through complex interactions between different cells of the immune system. In most autoimmune disorders, autoantigen-specific responses are induced by the activation of specific T cells with self peptides displayed on activated antigen presenting cells (APCs). These T cells may then activate and drive B cell responses that either initiate or contribute to chronic disease pathogenesis. In order to activate the T cell, two signals are required: T cell receptor (TCR) engagement by autoantigen presented in the context of self MHC class II and costimulation (CD28-CD80/CD86 interactions). Feedback must also be provided to the APC through MHC class II engagement by the TCR and through costimulatory events controlling T cell differentiation and effector function (CD154-CD40 interactions, among others). With this in mind, numerous strategies have been developed to block the engagement and activation of self-reactive cells. We review and discuss recent progress in understanding the efficacy and underlying molecular mechanisms of three separate immunotherapeutic strategies targeting the TCR and costimulatory molecules: i) blocking TCR signaling (using non-mitogenic anti-CD3 monoclonal antibody); ii) blocking CD28 costimulation (anti-B7 monoclonal antibody blockade); and iii) blocking CD40 engagement on APCs (anti-CD154 monoclonal antibody blockade).

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Prevention of T-cell activation by rhCTLA4-Ig and anti-CD40L monoclonal antibody results in indefinite islet allograft survival

Cited by 12 publications

References 4 publications

Prolonged Islet Graft Survival in NOD Mice by Blockade of the CD40-CD154 Pathway of T-Cell Costimulation

Prolonged Islet Graft Survival in NOD Mice by Blockade of the CD40-CD154 Pathway of T-Cell Costimulation

Inability to Induce Tolerance Through Direct Antigen Presentation

Therapeutic Blockade of TCR Signal Transduction and Co-Stimulation in Autoimmune Disease

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