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to be accompanied by a temporary course of therapy with Tacrolimus converted to Sirolimus (Tacro-Siro conversion) to be withdrawn at 12 months, and mycophenolate mofetil (MMF) to be withdrawn by 18 months postoperatively.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.
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