Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance

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, t...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2013-09, Vol.24 (9), p.1376-1385
Main Authors: LEVENTHAL, Joseph R, MATHEW, James M, KANWAR, Yashpal, ABECASSIS, Michael, MILLER, Joshua, SALOMON, Daniel R, KURIAN, Sunil M, SUTHANTHIRAN, Manikkam, TAMBUR, Anat, FRIEDEWALD, John, GALLON, Lorenzo, CHARETTE, Jane, LEVITSKY, Josh
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Biomarkers
Biopsy
Brief Communications
Chimerism
DNA - genetics
Female
Follow-Up Studies
Genome - genetics
Graft Rejection - immunology
Graft Rejection - prevention & control
Hematopoietic Stem Cell Transplantation
HLA Antigens - genetics
HLA Antigens - immunology
Humans
Immune Tolerance - immunology
Immunosuppressive Agents - therapeutic use
Kidney - pathology
Kidney Transplantation - immunology
Kidney Transplantation - pathology
Male
Medical sciences
Middle Aged
Nephrology. Urinary tract diseases
Retrospective Studies
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Summary: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 Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant).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.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2013010068