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

描述(申请人提供)：我们的假设是，最近确定了一系列与人类白细胞抗原基因完全相同(HLAgi)同胞肾移植的免疫激活和/或调节有关的多态等位基因，有关这些等位基因的知识可用于促进在使用供者特异性造血干细胞(DHSc)输注时持续获得强大的免疫耐受状态。这些多态编码次要组织相容性抗原(MHAgs)，也是我们在这里所称的“新的免疫反应基因”(‘NIR’基因)。它们编码Toll样受体(TLR)、杀伤Ig样受体(KIR)、细胞因子基因启动子多态(CGP)，包括单核苷酸(SNP)的DMA限制酶等位基因多态及其串联重复内含子特征(VNTR)，如IL-1受体拮抗剂(IL-1R？)(VNTR)和几个共刺激分子。如果这些系统的等位基因在供体或受体细胞/组织中表达(单独或联合表达)，可能会促进耐受机制或增强HLAGI移植免疫。因此，我们将在20对HLAGI兄弟姐妹供/受者肾移植配对中研究这些多重系统及其对T细胞调节/缺失和细胞和体液移植免疫激活的影响[目前全国范围内移植物10年存活率在65-70%之间，其中包括20%(免疫抑制相关的)死亡率]。具体目的I：为安全地诱导20例人类HLAGI同胞供肾移植受者的永久性免疫耐受，在两种剂量的Alemtuzumab(CamPath-1H，C1H)诱导后，通过四次DHSc输注CD34+选择的DHSc。这将伴随着一个临时疗程，他克莫司转换为西罗莫司(Tacro-Siro转换)，在术后12个月停用，霉酚酸酯(MMF)在术后18个月停用。第一次CD34+输注将在术后第5天，即第二次C1H治疗后一天进行。第二次DHSc输液将在Tacro转Siro后2-3个月内进行。第三次和第四次DHSc输液将在术后6个月和9个月进行。在停用免疫抑制药物之前，肾功能正常，移植肾活检静止。具体目的II：研究这些受者的耐受性/调节机制，在没有使用mhag和nIR1基因SSP分型的维持免疫抑制治疗以及几种HLAg/适应性检测嵌合体和调节或缺失效应的情况下，回过头来看会导致永久接受此类肾移植。就外行而言，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.