Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection.

Chandraker, Anil; Azuma, Haruhito; Nadeau, Kari; Carpenter, Charles B.; Tilney, Nicholas L.; Hancock, Wayne W.; Sayegh, Mohamed H.

doi:10.1172/jci2299

Cited by 120 publications

(70 citation statements)

References 53 publications

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“…Th1 and Th2 cytokines exert a mutual cross-regulation on the precursors of Th1-or Th2-type effector cells which are important mediators in directing the immune system towards the appropriate response. The selective activation of either Th1 or Th2 type cells depends on the antigen and is influenced by cytokines produced partly by antigenpresenting cells and partly by T helper cells (8). Both Th1 and Th2 cytokines are possibly susceptible to the herb activation or suppression (9).…”

Section: Effects On Cytokine Production and Other Immune Effector Cellsmentioning

confidence: 99%

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

Huang¹,

Lin

Liao

et al. 2008

Cell Mol Immunol

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In recent years, studies on evaluation of the therapeutic and toxic activity of herbal medicinal products became available and popular. The advances in modern biotechnology have led to discovery of many new active constituents. However, it is a constant challenge to establish the pharmacological basis for efficacy and safety of herbal medicinal products. A better understanding of the effects and bioavailability of phytopharmaceuticals can help in discovering suitable and rational therapies. In this review, we present the bioavailability studies in immune system that has been conducted for some of the more important or widely used phytopharmaceuticals. Furthermore, various new drug targets worthy of using for drug development in immunomodulating herbal medicine area and their regulatory mechanisms are also discussed. Adverse effects, drug interactions, and contraindications are also discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived pharmaceutical components. Cellular & Molecular Immunology. 2008;5(1):23-31.

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Section: Effects On Cytokine Production and Other Immune Effector Cellsmentioning

confidence: 99%

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

Huang¹,

Lin

Liao

et al. 2008

Cell Mol Immunol

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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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“…In vitro studies have demonstrated that CTLA4Ig-mediated blocking of CD80/86 results in the development of anergic T cells (16)(17)(18). In addition, the efficacy of CTLA-4Ig in prolonging allograft acceptance in rodent transplantation models suggests that abatacept treatment could promote T cell tolerance.…”

mentioning

confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection.

Cited by 120 publications

References 53 publications

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

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

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

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