SPECIFIC UNRESPONSIVENESS IN ORGAN TRANSPLANTATION

这个项目代表了一个共同的努力，探索有前途的 诱导移植物特异性免疫耐受的新方法 同种异体组织工作假设是， 免疫抑制疗法与抗原的结合提供了一种更好的治疗方法， 致耐受性形式将诱导持久的无应答状态， 需要很少或不需要持续治疗。实验工作表明， 通过用同种异体细胞预处理来提高移植物存活率， 在人类中以部分HLA匹配血液的形式部分复制 输血初步的动物工作，构成了部分的基础， 这项提议的结果表明，代表 MHC分子的多态性区域在注射 佐剂，但当喂入胃肠道或给予 静脉注射该作用由肽呈递启动， 受体（自身）MHC分子，似乎是由一种状态介导的， 涉及下调DTH、MLR的细胞亚群的主动免疫 增殖和移植排斥。项目#1将研究细胞 HLA定向单血受者诱导的免疫应答 输血，并利用选择的合成HLA I类和II类肽 在体外研究免疫原性和致耐受性潜力， 不同的应答者组合，导致临床 喂食或静脉给药以脱敏或耐受移植物的试验 候选人项目#2将使用功能上不同的知识 T细胞亚群，其携带代表替代形式的 表达的表面分子来设计选择性抑制的手段，或 刺激T细胞亚群。在某种程度上，环孢素 选择性，这使抑制型细胞不受影响，但更高程度的 选择性是理想的。由于细胞表面的独特组合 分子似乎定义了一个子集， 双功能杂交单克隆抗体，沿着新的和高度 将细胞毒素连接到单克隆抗体的有效方法现在使得有可能 以前所未有的方式操纵细胞免疫反应。 项目#3将分别测试和组合测试MHC肽和 在小鼠和恒河猴模型中的新型双功能mAb。的 从这些实验中获得的知识将导致新的临床 试验，也可能对一些自身免疫性疾病有影响。

This program project represents a concerted effort to explore promising new means for inducing specific immunological tolerance to transplanted allogeneic tissue. The working assumption is that more selective immunosuppressive therapy combined with antigen provided in a more tolerogenic form will induce states of lasting unresponsiveness, requiring little or no continuing therapy. Experimental work showing enhanced graft survival by pre-treatment with allogeneic cells has been partially reproduced in humans in the form of partial HLA matched blood transfusions. The preliminary animal work which forms the basis for part of this proposal shows that synthetic peptides representing the polymorphic regions of MHC molecules immunize when injected with adjuvant, but are quite tolerogenic when fed into the GI tract, or given intravenously. The effect is initiated by peptide presentation by recipient (self) MHC molecules and appears to be mediated by a state of active immunity involving subsets of cells which down-regulate DTH, MLR proliferation, and graft rejection. Project #1 will study the cellular response induced in recipients of HLA directed single blood transfusions, and utilize selected synthetic HLA class I and II peptides in vitro to study the immunogenicity and tolerogenic potential in different responder combination, leading to a rationale for clinical trials of feeding or IV dosing to desensitize or tolerize transplant candidates. Project #2 will use knowledge on functionally different subsets of T cells which bear markers representing alternative forms of expressed surface molecules to design means of selective inhibition or stimulation of T cell subsets. To some extent cyclosporine has selectivity which spares suppressor type cells, but a higher degree of selectivity is desirable. Since unique combination of cell surface molecules seem to define a subset, the technology of producing bifunctional hybrid monoclonal antibodies, along with new and highly efficient means of linking cell toxins to mAbs now make it possible to manipulate cellular immune responses in ways not previously possible. Project #3 will test separately, and in combination, MHC peptides and the new bifunctional mAbs in mouse and rhesus monkey models. The knowledge gained from these experiments should lead to novel clinical trials, and could also have implications for some autoimmune diseases.