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be accompanied by a temporary course of therapy with Tacrolimus converted to Sirolimus (Tacro-Siro conversion) to be withdrawn at 12 months, and mycophenolate mofetil (MMF) to be withdrawn by 18 months postoperatively.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

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025243-28
Application #
7918916
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Flessner, Michael Francis
Project Start
1978-07-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2013-06-30
Support Year
28
Fiscal Year
2010
Total Cost
$566,792
Indirect Cost
Name
Northwestern University at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Leventhal, Joseph R; Miller, Joshua; Mathew, James M et al. (2018) Updated follow-up of a tolerance protocol in HLA-identical renal transplant pairs given donor hematopoietic stem cells. Hum Immunol 79:277-282
Leventhal, J R; Mathew, J M; Salomon, D R et al. (2016) Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers. Am J Transplant 16:221-34
Levitsky, Josh; Miller, Joshua; Huang, Xuemei et al. (2013) Inhibitory effects of belatacept on allospecific regulatory T-cell generation in humans. Transplantation 96:689-96
Leventhal, Joseph R; Mathew, James M; Salomon, Daniel R et al. (2013) Genomic biomarkers correlate with HLA-identical renal transplant tolerance. J Am Soc Nephrol 24:1376-85
Leventhal, J; Miller, J; Abecassis, M et al. (2013) Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance. Clin Pharmacol Ther 93:36-45
Levitsky, Josh; Mathew, James M; Abecassis, Michael et al. (2013) Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology 57:239-48
Leventhal, Joseph; Abecassis, Michael; Miller, Joshua et al. (2012) Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 4:124ra28
Levitsky, Josh; Leventhal, Joseph R; Miller, Joshua et al. (2012) Favorable effects of alemtuzumab on allospecific regulatory T-cell generation. Hum Immunol 73:141-9
Mathew, James M; Leventhal, Joseph R; Miller, Joshua (2011) Microchimerism in promoting graft acceptance in clinical transplantation. Curr Opin Organ Transplant 16:345-52
Yu, Yuming; Miller, Joshua; Leventhal, Joseph R et al. (2011) Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR. PLoS One 6:e22450

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