Article

IDO and Regulatory T Cell Support Are Critical for Cytotoxic T Lymphocyte-Associated Ag-4 Ig-Mediated Long-Term Solid Organ Allograft Survival

Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, A-6020 Innsbruck, Austria.
The Journal of Immunology (Impact Factor: 5.36). 11/2011; 188(1):37-46. DOI: 10.4049/jimmunol.1002777
Source: PubMed

ABSTRACT Costimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig upregulates expression of the immunoregulatory enzyme IDO in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. In this study, we studied whether concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor-specific transfusion showed indefinite graft survival (>100 d) without signs of chronic rejection or donor specific Ab formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared with rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-dl-tryptophan, either at transplant or at postoperative day 50, abrogated CTLA4Ig + DST-induced long-term graft survival. Importantly, IDO1 knockout recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of regulatory T cells (Tregs) resulted in decreased IDO activity and again prevented CTLA4Ig + DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this costimulatory blocker.

0 Followers
 · 
143 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mouse models are of special interest in research since a wide variety of monoclonal antibodies and commercially defined inbred and knockout strains are available to perform mechanistic in vivo studies. While heart transplantation models using a suture technique were first successfully developed in rats, the translation into an equally widespread used murine equivalent was never achieved due the technical complexity of the microsurgical procedure. In contrast, non-suture cuff techniques, also developed initially in rats, were successfully adapted for use in mice(1-3). This technique for revascularization involves two major steps I) everting the recipient vessel over a polyethylene cuff; II) pulling the donor vessel over the formerly everted recipient vessel and holding it in place with a circumferential tie. This ensures a continuity of the endothelial layer, short operating time and very high patency rates(4). Using this technique for vascular anastomosis we performed more than 1,000 cervical heart transplants with an overall success rate of 95%. For arterial inflow the common carotid artery and the proximal aortic arch were anastomosed resulting in a retrograde perfusion of the transplanted heart. For venous drainage the pulmonary artery of the graft was anastomosed with the external jugular vein of the recipient(5). Herein, we provide additional details of this technique to supplement the video.
    Journal of Visualized Experiments 01/2014; DOI:10.3791/50753
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Sackler Institute for Nutrition Science and the World Health Organization (WHO) have worked together to formulate a research agenda for nutrition science. Undernutrition of children has profound effects on health, development, and achievement of full human capacity. Undernutrition is not simply caused by a lack of food, but results from a complex interplay of intra- and intergenerational factors. Representative preclinical models and comprehensive well-controlled longitudinal clinical studies are needed to further understand the contributions and the interrelationships among these factors and to develop interventions that are effective and durable. This paper summarizes work on mechanisms underlying the varied manifestations of childhood undernutrition and discusses current gaps in knowledge and challenges to our understanding of undernutrition and infection/immunity throughout the human life cycle, focusing on early childhood growth. It proposes a series of basic and clinical studies to address this global health challenge.
    Annals of the New York Academy of Sciences 08/2014; DOI:10.1111/nyas.12487 · 4.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: T cell activation is a key event in the adaptive immune response and vital to the generation of both cellular and humoral immunity. Activation is required not only for effective CD4 T cell responses but also to provide help for B cells and the generation of cytotoxic T cell responses. Unsurprisingly, impaired T cell activation results in infectious pathology, whereas dysregulated activation can result in autoimmunity. The decision to activate is therefore tightly regulated and the CD28/CTLA-4 pathway represents this apical decision point at the molecular level. In particular, CTLA-4 (CD152) is an essential checkpoint control for autoimmunity; however, the molecular mechanism(s) by which CTLA-4 achieves its regulatory function are not well understood, especially how it functionally intersects with the CD28 pathway. In this chapter, we review the established molecular and cellular concepts relating to CD28 and CTLA-4 biology, and attempt to integrate these by discussing the transendocytosis of ligands as a new model of CTLA-4 function.
    Advances in Immunology 01/2014; 124C:95-136. DOI:10.1016/B978-0-12-800147-9.00004-2 · 5.53 Impact Factor