Immunobiology of Pancreatic Islet Xenografting

胰岛异种移植的免疫生物学

• 批准号: 6706328
• 负责人: Ronald G Gill
• 金额: $ 20.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706328
• 关键词: Immunobiology; Pancreatic; Islet; Xenografting

DESCRIPTION (provided by applicant): A key dilemma facing organ and tissue grafting is the shortage of donor tissues for transplantation. This problem has led to the consideration of xenogeneic tissues as an alternative supply of donor material. The aim of this proposal is to understand the nature of T cell-dependent immunity/tolerance to xenogeneic pancreatic islets as a model of cellular xenotransplantation. Our general working hypothesis has been that islet allograft rejection is dominated by donor APC-dependent 'direct' recognition while xenograft rejection is dominated by host APC dependent 'indirect' recognition. Based on this supposition, we had proposed that the nature of tolerance to islet allografts and xenografts might be quite distinct. However, many studies increasingly suggest that host MHC class II-restricted (indirect) antigen presentation may be of primary general importance in peripheral tolerance. Thus, xenograft tolerance and allograft tolerance may not be as distinct as we once imagined. Consistent with this view, we have found that robust therapies for inducing islet allograft tolerance are nearly as efficacious for inducing long-term rat and porcine islet xenograft survival in mice. In particular, we have found that combined therapy with anti-LFA-1 (CDlla) plus anti-CD154 monoclonal antibodies can lead to consistent long-term allograft, and rat or porcine xenograft acceptance in high-responder mouse strains. A key goal of this proposal will be to determine if putative properties of peripheral allograft tolerance also apply to 'rules' governing xenograft 'tolerance' in vivo. To this end, this proposal has the following specific aims: (1) Determine whether long-term xenograft acceptance is associated with regulatory tolerance in vivo: This aim will test the simple hypothesis that xenograft tolerance induced in adult animals results is due dominant, regulatory tolerance. (2) Determine the cellular requirements for long-term xenograft acceptance/tolerance. This Aim will test the hypothesis that long term xenograft acceptance requires the active participation of lymphoid subpopulations including CD4 T cells, CDl-restricted 'invariant' (TcR Jalpha281+) NKT cells, and B cells, and (3) Determine whether IFNgamma is necessary for xenograft acceptance/tolerance. This Aim will test the hypothesis that, unlike several models of allograft tolerance, xenograft tolerance will be IFNgamma-independent in vivo.

描述（由申请人提供）： 器官和组织移植面临的一个关键困境是缺乏用于移植的供体组织。这个问题导致考虑异种组织作为供体材料的替代供应。本提案的目的是了解异种胰岛作为细胞异种移植模型的T细胞依赖性免疫/耐受的性质。我们一般的工作假设是，胰岛移植排斥反应主要是由供体APC依赖的“直接”识别，而异种移植排斥反应主要是由宿主APC依赖的“间接”识别。基于这一假设，我们曾提出同种异体胰岛移植和异种胰岛移植耐受的性质可能是完全不同的。然而，越来越多的研究表明，宿主MHC II类限制性（间接）抗原呈递在外周耐受中可能具有首要的普遍重要性。因此，异种移植耐受性和同种移植耐受性可能并不像我们曾经想象的那样截然不同。与这一观点一致，我们发现诱导胰岛同种异体移植耐受的稳健疗法对于诱导小鼠中的长期大鼠和猪胰岛异种移植物存活几乎同样有效。特别地，我们已经发现，用抗LFA-1（CD 11 a）加抗CD 154单克隆抗体的联合治疗可以导致一致的长期同种异体移植物，以及高应答小鼠品系中的大鼠或猪异种移植物接受。这项建议的一个关键目标是确定外周同种异体移植物耐受性的假定特性是否也适用于体内异种移植物耐受性的“规则”。为此，本提案具有以下具体目标：（1）确定长期异种移植物接受是否与体内调节性耐受相关：该目标将检验以下简单假设：成年动物中诱导的异种移植物耐受结果是由于显性调节性耐受。(2)确定长期异种移植物接受/耐受的细胞要求。该目的将检验长期异种移植物接受需要淋巴亚群的积极参与的假设，所述淋巴亚群包括CD 4 T细胞、CD 1限制性“不变”（TcR J α 281+）NKT细胞和B细胞，和（3）确定IFN γ是否是异种移植物接受/耐受所必需的。该目的将检验以下假设：与几种同种异体移植物耐受模型不同，异种移植物耐受将是体内IFN γ非依赖性的。