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

HLA 相同肾移植中的供体干细胞、Campath、T/B 细胞调节

• 批准号: 7316210
• 负责人: Joshua Miller
• 金额: $ 55.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316210
• 关键词: Alleles; Antibodies; B-Lymphocytes; Biological Assay; Biopsy; Bone Marrow; CD28 gene; CD34 gene; CSF3 gene; Cells; Cellular Assay; Chimerism; Clinical; Clinical Protocols; Collaborations; Cytokine Gene; Cytokine Receptor Gene; Development; Dose; Engraftment; Exclusion; Foundations; Genes; Genetic; Genetic Polymorphism; Goals; Graft Survival; Hematopoietic stem cells; Human; Immune; Immune Response Genes; Immune Tolerance; Immune response; Immunity; Immunosuppression; Infusion procedures; Interleukin-1 Receptors; Interleukin-1 alpha; Introns; Kidney Transplantation; Knowledge; Laboratories; Link; Los Angeles; MabCampath; Maintenance; Messenger RNA; Minisatellite Repeats; Minor Histocompatibility Antigens; Molecular; Monitor; Monoclonal Antibody Campath-1H; Nested PCR; Netherlands; Operative Surgical Procedures; Progress Reports; Proteomics; Protocols documentation; Regulation; Renal function; Research Institute; Risk; Series; Siblings; Single Nucleotide Polymorphism; Sirolimus; Stem cells; System; T cell regulation; T-Lymphocyte; Tacrolimus; Tandem Repeat Sequences; Therapeutic immunosuppression; Tissues; Toll-Like Receptor 5; Toll-like receptor 6; Toll-like receptors; Transplantation; Withdrawal; alemtuzumab; anakinra; cost; day; drug withdrawal; mortality; mycophenolate mofetil; peripheral blood; promoter; prospective; receptor; restriction enzyme

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.

描述（由申请人提供）：我们的假设是，最近定义了一系列涉及 HLA 基因相同（HLAgi）同级肾移植中的免疫激活和/或调节的多态性等位基因，有关这些的知识可用于在使用供体特异性造血干细胞（DHSC）输注时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（mHAgs），以及我们在本文中称为“新免疫应答基因”（“nIR”基因）的东西。这些编码 Toll 样受体 (TLR)、杀伤性 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 DMA 限制性酶等位基因多态性及其串联重复内含子特征 (VNTR)，例如 IL-1 受体拮抗剂 IL-1 α/β (SNP) 的内含子特征 (VNTR) (IL-1r?) (VNTR) 和几种共刺激分子，分别。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），可能会促进耐受机制或增强 HLAgi 移植免疫力。因此，我们将在 20 个 HLAgi 同胞供体/受体肾移植对中研究这些多重系统，及其对 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 10 年移植物存活率为 65-70%，包括 20%（免疫抑制相关）死亡率]。具体目标 I：在用两剂阿仑单抗（Campath-1H、C1H）诱导后，通过四次 DHSC 输注 CD34+ 选择的 DHSC，在 20 名人类 HLAgi 同胞供体肾移植受者中安全诱导永久免疫耐受。这将伴随一个临时疗程，将他克莫司转换为西罗莫司（Tacro-Siro 转换），并在术后 12 个月停用，吗替麦考酚酯 (MMF) 在术后 18 个月停用。第一次 CD34+ 输注将于术后第 5 天（第二次 C1H 治疗后一天）进行。第二次 DHSC 输注将于从 Tacro 转换为 Siro 术后两到三个月内进行。第三次和第四次 DHSC 输注将在术后六个月和九个月时进行。在肾功能正常和静止移植活检之前，将停止免疫抑制。具体目标 II：研究在这些受者中起作用的耐受性/调节机制，回顾起来，在没有使用 mHAg 和 nIR1 基因 SSP 分型的维持免疫抑制治疗的情况下，这些机制将导致永久接受此类肾移植，以及使用 mHAg 和 nIR1 基因 SSP 分型，以及一些用于嵌合和调节或缺失效应的 HLAg/适应性测定。通俗地说，目标是消除长期免疫抑制的风险和成本。