Immunobiology of Pancreatic Islet Xenografting

描述(由申请人提供)： 器官和组织移植面临的一个关键难题是供移植的供体组织短缺。这一问题导致了异种组织作为供体材料的替代供应的考虑。这项建议的目的是了解T细胞依赖免疫/耐受异种胰岛作为细胞异种移植模型的本质。我们的一般工作假设是，同种异体胰岛移植排斥反应主要是供体APC依赖的“直接”识别，而异种移植排斥反应主要是宿主APC依赖的“间接”识别。基于这一假设，我们提出了对同种异体胰岛移植物和异种移植物的耐受性可能是截然不同的。然而，越来越多的研究表明，宿主MHC II类限制性(间接)抗原提呈在外周耐受中可能具有重要的普遍意义。因此，异种移植耐受和同种移植耐受可能并不像我们曾经想象的那样不同。与这一观点一致，我们发现诱导同种异体胰岛移植耐受的强有力的治疗方法对于诱导小鼠异种胰岛移植的长期存活几乎同样有效。特别是，我们发现用抗LFA-1(CD11a)和抗CD154单抗联合治疗可以导致长期一致的同种异体移植，以及对高应答小鼠品系的大鼠或猪异种移植的接受。这项提案的一个关键目标将是确定外周同种异体移植耐受性的推定特性是否也适用于体内异种移植耐受性的“规则”。为此，这项建议有以下具体目的：(1)确定长期异种移植接受是否与体内调节性耐受有关：这一目的将检验一个简单的假设，即成年动物诱导的异种移植耐受结果是应有的显性、调节性耐受。(2)确定长期接受/耐受异种移植物的细胞需求。这一目标将检验长期异种移植接受需要包括CD4T细胞、CDL限制性‘不变’(TCR Jalpha281+)NKT细胞和B细胞在内的淋巴亚群的积极参与的假说，以及(3)确定异种移植接受/耐受是否需要干扰素-γ。这一目标将检验这样一种假设，即与几种同种移植耐受模型不同，异种移植耐受在体内将不依赖于IFN-γ。

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.