Donor Stem Cells, Campath, T/B Cell Regulation In HLA-Identical Renal Transplants

描述（由申请人提供）：我们的假设是，在HLA遗传学相同（HLAgi）的同胞肾移植中，最近定义了一系列参与免疫激活和/或调节的几种多态性等位基因，当使用供体特异性造血干细胞（DHSC）输注时，关于这些等位基因的知识可用于促进一致地实现稳健的免疫耐受状态.多态性编码次要组织相容性抗原（mHAg），以及我们在本文中称为“新免疫应答基因”（“nIR”基因）的基因。这些编码toll样受体（TLR）、杀伤Ig样受体（KIR）、细胞因子基因启动子多态性（CGP），包括单核苷酸（SNP）的DNA限制酶等位基因多态性及其串联重复内含子表征（VNTR），例如IL-1 α/β（SNP）、IL-1受体拮抗剂（IL-1 r？）（VNTR）和几种共刺激分子。这些系统的等位基因，如果在供体或受体细胞/组织中表达（单独或组合），可能促进致耐受性机制或放大HLAgi移植免疫。因此，我们将在20个HLAgi同胞供者/受者肾移植对中研究这些多系统，以及它们对T细胞调节/缺失与细胞和体液移植免疫激活的影响[目前全国范围内的10年移植物存活率在65-70%之间，包括20%（免疫抑制相关）死亡率]。具体目标一：在20例人类HLAgi同胞供体肾移植受者中安全诱导永久性免疫耐受，在用两个剂量的阿仑单抗（Campath-1H，C1 H）诱导后，给予4次CD 34+选择的DHSC的DHSC输注。这将伴随一个临时疗程，他克莫司转换为西罗莫司（他克-西罗转换），在术后12个月时停用，霉酚酸酯（MMF）在术后18个月时停用。第一次CD 34+输注将在术后第5天，即第二次C1 H治疗后1天进行。第二次DHSC输注将在从Tacro转换为Siro后2 - 3个月进行。第三次和第四次DHSC输注将在术后6个月和9个月进行。在肾功能正常和静止期移植活检后，将停用免疫抑制剂。具体目标二：使用mHAg和nIR 1基因SSP分型以及几种HLAg/适应性嵌合体和调节或缺失效应检测，研究这些受体中的致耐受性/调节机制，回顾性研究这些机制在缺乏维持免疫抑制治疗的情况下会导致永久接受此类肾移植。通俗地说，目标是消除长期免疫抑制的风险和成本。

DESCRIPTION (provided by applicant): Our hypothesis is that there are recently defined series of several polymorphic alleles involved in immune activation and/or regulation in HLA genetically identical (HLAgi) sibling renal transplants, knowledge about which can be used to facilitate consistently achieving a state of robust immunologic tolerance when donor- specific hematopoietic stem cell (DHSC) infusion is used. The polymorphisms encode minor histocompatibility antigens (mHAgs), and also what we designate herein as "new immune response genes" ('nIR' genes). These encode toll-like receptors (TLR), killer Ig-like receptors (KIR), cytokine gene promoter polymorphisms (CGP), including DMA restriction enzyme allelic polymorphisms of single nucleotides (SNP) and their tandem repeat intron characterization (VNTR) such as those for IL-1 alpha/beta (SNP), the IL-1 receptor antagonist (IL-1r?) (VNTR) and several co-stimulatory molecules, respectively. Alleles of these systems, if expressed (singly or in combination) in donor or recipient cells / tissues, might either facilitate tolerogenic mechanisms or amplify HLAgi transplantation immunity. We therefore will study these multiple systems, and their effects on T cell regulation/deletion vs. activation of cellular and humoral transplantation immunity, in 20 HLAgi sibling donor / recipient renal transplant pairs [current nation-wide 10-year graft survival is between 65-70% including 20% (immunosuppression-related) mortality]. Specific Aim I: To safely induce permanent immunologic tolerance in 20 recipients of human HLAgi sibling donor renal transplants, by administering four DHSC infusions of CD34+ selected DHSC after induction with two doses of Alemtuzumab (Campath-1H, C1H). This is to be accompanied by a temporary course of therapy with Tacrolimus converted to Sirolimus (Tacro-Siro conversion) to be withdrawn at 12 months, and mycophenolate mofetil (MMF) to be withdrawn by 18 months postoperatively. The first CD34+ infusion is to be administered on Day 5 postoperatively, one day after the second C1H treatment. The second DHSC infusion is to be given between two and three months postoperatively after conversion from Tacro to Siro. The third and fourth DHSC infusions are to be given at six and nine months postoperatively. Withdrawal of immunosuppression will be preceded by normal renal function and quiescent transplant biopsies. Specific Aim II: To study tolerogenic/regulatory mechanisms operative in these recipients that would in retrospect have caused permanent acceptance of such renal transplants in the absence of maintenance immunosuppressive therapy using mHAg and nIR1 gene SSP typing, as well as several HLAg/ adapted assays for chimerism and regulatory or deletional effects. The goal in lay terms is to eliminate long-term immunosuppression risks and costs.