T-Cell Costimulatory Blockade in Organ Transplantation

Turka, Laurence A.

doi:10.1101/cshperspect.a015537

Cited by 16 publications

(10 citation statements)

References 106 publications

(97 reference statements)

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“…It is essential to notice that spleen cells DST is more efficient than bone marrow cells DST in regulation induction. 22 Before injection and after 24 hours, we used a dial-thickness gauge to measure footpad thickness; change in thickness, after subtraction of PBS value [net swelling] was expressed in units of 1.0 × 10 −4 inches. To determine the extent of “linked suppression” we used the following formula:…”

Section: Methodsmentioning

confidence: 99%

Kinetics of Alloantigen-Specific Regulatory CD4 T Cell Development and Tissue Distribution After Donor-Specific Transfusion and Costimulatory Blockade

Tomita

Satomi

Baran

et al. 2016

Transplantation Direct

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BackgroundThe influence of donor-side regulation toward recipient antigens on graft outcome is poorly understood.MethodsBecause this influence might be due in part to the accumulation of tissue-resident memory T cells in the donor organ, we used a standard murine tolerization model (donor-specific transfusion plus CD40L blockade) to determine the kinetics of development and peripheralization of allospecific regulatory T cell in lymphoid tissues and liver, a secondary lymphoid organ used in transplantation.ResultsWe found that donor-specific transfusion and CD40L blockade leads to a progressive and sustained T regulatory allospecific response. The cytokines IL10, TGFβ, and IL35 all contributed to the regulatory phenomenon as determined by trans vivo delayed hypersensitivity assay. Unexpectedly, an early and transient self-specific regulatory response was found as well. Using double reporter mice (forkhead box p 3 [Foxp3]-yellow fluorescent protein, Epstein-Barr virus-induced gene 3 [Ebi3]-TdTomRed), we found an increase in Foxp3+CD25+ regulatory T (Treg) cells paralleling the regulatory response. The Ebi3+ CD4 T cells (IL35-producing) were mainly classic Treg cells (Foxp3+CD25+), whereas TGFβ+ CD4 T cells are mostly Foxp3-negative, suggesting 2 different CD4 Treg cell subsets. Liver-resident TGFβ+ CD4 T cells appeared more rapidly than Ebi3-producing T cells, whereas at later timepoints, the Ebi3 response predominated both in lymphoid tissues and liver.ConclusionsThe timing of appearance of donor organ resident Treg cell subsets should be considered in experiments testing the role of bidirectional regulation in transplant tolerance.

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Section: Methodsmentioning

confidence: 99%

Kinetics of Alloantigen-Specific Regulatory CD4 T Cell Development and Tissue Distribution After Donor-Specific Transfusion and Costimulatory Blockade

Tomita

Satomi

Baran

et al. 2016

Transplantation Direct

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“…By exploiting the higher affinity of CTLA-4 for its ligands, these compounds have been shown to inhibit T cell responses in models of autoimmune disease and in transplantation models (38,39).…”

Section: Ligand Blockadementioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

100

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T cell activation is a key event in the adaptive immune system and vital in the generation of protective cellular and humoral immunity. Activation is required to generate CD4 effector T cell responses and provide help for B cell and cytotoxic T cell responses. While defective T responses to foreign antigen result in infectious pathology, over-reactive T cell responses against self-antigens result in autoimmunity and, in a transplantation setting, tissue rejection. Understanding how T cell activation is normally regulated is critical to therapeutic intervention and the CD28/CTLA-4 (CD152) pathway represents the initial activation checkpoint in molecular terms. In particular, while the CTLA-4 pathway is well established as an essential regulator of self-reactivity, its mechanism of action is still uncertain. Such mechanistic issues are important given its central position in T cell activation and the increasing number of therapeutic modalities aimed at manipulating the CD28/CTLA-4 pathway. Here, we provide an updated view of CTLA-4 biology, reviewing the established features of the system and highlighting its interplay with CD28. We then discuss how recent progress in our understanding of this pathway affects our interpretations following intervention. A Functional Overview of the CD28/CTLA-4 Pathway CD28 is expressed on the surface of the majority of na€ ıve CD4 and CD8 T cells and is the major costimulatory molecule in initial T cell activation. Together with engagement of the T cell receptor CD28 ligation results in the augmentation of many aspects of T cell-mediated immunity (1-3). Consequently, mice deficient in CD28 show an array of immune defects including impaired T cell activation, a lack of T cell help for B cells and poor memory T cell responses, all highlighting the importance of CD28 costimulation in the generation of effective T cell responses and immune memory.The immune stimulatory features of the CD28 pathway are triggered by engagement of two well-described ligands found on antigen-presenting cells (4). The two ligands CD80 (B7/BB1 or B7-1) and CD86 (B7-2) were, until recently, thought to be the sole ligands for CD28 and CTLA-4; however, there are recent reports that human (but not mouse) CD28 and CTLA-4, can also bind to the ICOS ligand (5). In addition, the PD-1 ligand, PD-L1 can also interact with CD80 (6). The significance of these novel interactions is still emerging and will not be discussed further here. Importantly, the expression of CD80 and CD86 is up-regulated in response to inflammatory stimuli including Toll-like receptor stimulation. As such, up-regulation of ligands is seen as a key link between innate ''danger'' signals and the triggering of an effective adaptive immune response (7). Despite structural and affinity differences (8) which would suggest functional differences, to date, the current view is that CD80 and CD86 have largely redundant or overlapping functions as represented in Figure 1 (9,10).In addition to binding to CD28, both CD80 and CD86 also bind to the inhibitory p...

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“…For CD4+ T cells to respond to alloantigen, they must be stimulated through the T‐cell receptor (Signal 1) and also receive additional signals (Signal 2) resulting in a net activation. Signal 2 is best known as “costimulation.” A family of therapeutics has been described that block costimulation and thus mitigate T‐cell activation in the presence of foreign antigen (termed costimulatory blockade) . Although multiple costimulatory pathways have now been described, ligation of CD28 on T cells by B71 and/or B72 on antigen‐presenting cells (APCs) is a major pathway, and it is required for adaptive immunity in a number of immune settings .…”

mentioning

confidence: 99%

“…Fusion proteins linking the extracellular domain of CTLA4 to an IgG tail have been developed, which cover B71/B72 and prevent ligation of CD28 on T cells. This approach (termed costimulatory blockade) has been used to decrease alloimmunization in the context of solid organ transplantation . Two variants of CTLA4‐Ig have now been FDA approved in humans for the treatment of rheumatoid arthritis and for prevention of solid organ transplantation, respectively …”

mentioning

confidence: 99%

Transfusion‐induced alloimmunization and platelet refractoriness in a mouse model: mechanisms and interventions

et al. 2015

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T-Cell Costimulatory Blockade in Organ Transplantation

Cited by 16 publications

References 106 publications

Kinetics of Alloantigen-Specific Regulatory CD4 T Cell Development and Tissue Distribution After Donor-Specific Transfusion and Costimulatory Blockade

Kinetics of Alloantigen-Specific Regulatory CD4 T Cell Development and Tissue Distribution After Donor-Specific Transfusion and Costimulatory Blockade

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Transfusion‐induced alloimmunization and platelet refractoriness in a mouse model: mechanisms and interventions

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