title: Genomic biomarkers correlate with HLA-identical renal transplant tolerance.
abstract: The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4(+)CD25(high)CD127(-)FOXP3(+) regulatory T cells and CD19(+)IgD/M(+)CD27(-) B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.
authors.affiliation: Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Leventhal
authors.forename: James M
authors.initials: JM
authors.lastname: Mathew
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Salomon
authors.forename: Sunil M
authors.initials: SM
authors.lastname: Kurian
authors.forename: Manikkam
authors.initials: M
authors.lastname: Suthanthiran
authors.forename: Anat
authors.initials: A
authors.lastname: Tambur
authors.forename: John
authors.initials: J
authors.lastname: Friedewald
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: Jane
authors.initials: J
authors.lastname: Charette
authors.forename: Josh
authors.initials: J
authors.lastname: Levitsky
authors.forename: Yashpal
authors.initials: Y
authors.lastname: Kanwar
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
mesh_terms: D000328:Adult; D015415:Biomarkers; D001706:Biopsy; D046528:Chimerism; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016678:Genome / Q000235:genetics*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D004247:DNA