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Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance

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Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance BRIEF COMMUNICATION www.jasn.org Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance † ‡ ‡ Joseph R. Leventhal,* James M. Mathew,* Daniel R. Salomon, Sunil M. Kurian, | | Manikkam Suthanthiran,§ Anat Tambur,* John Friedewald,* Lorenzo Gallon,* Jane Charette,* † Josh Levitsky,*¶ Yashpal Kanwar,** Michael Abecassis,* and Joshua Miller* *Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Departments of †Microbiology-Immunology and **Pathology, Northwestern University Feinberg School of Medicine, Chicago Illinois; ‡Department of Molecular and Experimental Medicine, The Scripps Research Institute and Scripps Center for Organ Transplantation, La Jolla, California; §Department of Transplantation Medicine, Weill Cornell Medical College, New York, New York; and Divisions of |Nephrology and ¶Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois ABSTRACT The ability to achieve immunologic tolerance after transplantation is a therapeutic disease recurrence, and continued immu- goal. Here, we report interim results from an ongoing trial of tolerance in HLA- nosuppression. The remaining three pa- identical sibling renal transplantation. The immunosuppressive regimen included tients had (subclinical) biopsy rejection alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycopheno- after complete withdrawal (Figure 1, C late immunosuppression converted to sirolimus, and complete drug withdrawal by and D, and Tables 1 and 2), and immuno- 24 months post-transplantation. Recipients were considered tolerant if they had suppression was reinstated, solely based normal biopsies and renal function after an additional 12 months without immuno- on the biopsies, without increase in panel suppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up reactive antibodies (PRAs) or positive after transplantation. Five of these 10 recipients had immunosuppression success- donor-specific crossmatches, and with fully withdrawn for 16–36 months (tolerant), 2 had disease recurrence, and 3 had unchanged serum creatinine concentra- subclinical rejection in protocol biopsies (nontolerant). Microchimerism disap- tions. The other 10 enrollees have not 2 peared after 1 year, and CD4+CD25highCD127 FOXP3+ regulatory T cells and yet reached 36 months. 2 CD19+IgD/M+CD27 B cells were increased through 5 years post-transplantation The total number of donor CD34+ in both tolerant and nontolerant recipients. Immune/inflammatory gene expression purified cells infused ranged between pathways in the peripheral blood and urine, however, were differentially downregu- 3.74 and 14.403106/kg recipient body lated between tolerant and nontolerant recipients. In summary, interim results from weight. Only temporary PBMC chime- this trial of tolerance in HLA-identical renal transplantation suggest that predictive rism was observed during the first year genomic biomarkers, but not immunoregulatory phenotyping, may be able to dis- (not above 3%), unrelated to tolerance criminate tolerant from nontolerant patients. or nontolerance (Table 1). Prolonged 2 CD4+ T cell depression (P,1.0310 7; J Am Soc Nephrol 24: 1376–1385, 2013. doi: 10.1681/ASN.2013010068 Received January 17, 2013. Accepted April 1, 2013. J.R.L. and J.M.M. contributed equally to this work We describe an HLA-identical tolerance 24-month biopsy (Figure 1). We herein and should both be considered first authors. 1–4 trial the without any myeloablation, evaluate the first 10 of 20 patients en- Published online ahead of print. Publication date but with four immunoselected CD34+ rolled, 5 of which passed the 36-month available at www.jasn.org. donor hematopoietic stem cell (DHSC) post-transplant milestone, with normal Correspondence: Dr. Joshua Miller, Comprehen- infusions in the first 9 months after renal biopsies one year after complete immuno- sive Transplant Center, Department of Surgery, transplantation.5,6 Temporary immuno- suppression withdrawal, designated as tol- Northwestern University Feinberg School of Medi- cine, Tarry Building 11-713 MCT 231, 300 East suppression consisted of alemtuzumab erant (Figure 1B and Tables 1 and 2). Two Superior Street, Chicago, IL 60611. Email: joshua- induction, tacrolimus/mycophenolate of the remaining five patients, designated [email protected] converted to sirolimus, followed by as nontolerant (see clinical summaries in Copyright © 2013 by the American Society of complete withdrawal after a normal the Supplemental Material), had renal Nephrology 1376 ISSN : 1046-6673/2409-1376 JAmSocNephrol24: 1376–1385, 2013 www.jasn.org BRIEF COMMUNICATION significance, not mapping to any coher- ent set of molecular pathways, suggest- ing that patients were not significantly different pretransplantation. In contrast, 1095 and 857 genes were differentially expressed (P,0.001), 1 year (sirolimus conversion) and 2 years (complete with- drawal) post-transplantation, and map- ped significantly (P,0.05) to 35 and 47 molecular functional pathways, respec- tively (Supplemental Material). Strik- ingly, differential gene expression for these two time points mapped to differ- ent pathways (Supplemental Figure 1). Of the 1095 and 857 differentially ex- pressed genes, 55% and 42% were downregulated in tolerant versus nonto- lerant patients respectively, specifically for inflammatory genes (65% and 35%, respectively). The better suppression of the 1-year signature in the tolerant group may signal/favor tolerance devel- opment and, at this early point post- transplantation, the opportunity to safely continue weaning immunosup- pression, whereas the 2-year signature may be more reflective of weaning im- Figure 1. Experimental tolerance inducing protocol and representative milestone tolerant munosuppression, but not indicative of and nontolerant biopsies. (A) Planned tolerance trial protocol timeline for treatment pro- failure of tolerance assessed 1 year later. cedures and monitoring of HLA-identical recipients up to 5 years postoperatively. (B) H&E We also identified four functional path- stain of the 36-month transplant biopsy of patient 2 (Table 1) reads as normal 12 months ways that were differentially shared after immunosuppression is withdrawn. This is also typical for patients 5, 6, 8, and 9 (i.e., the tolerant group) (Tables 1 and 2). (C) H&E stain of the transplant biopsy of patient 1 (Table 1) between tolerant and nontolerant recip- reads as Banff 1A acute rejection (with normal renal function) obtained after 12 months off ients by comparing differential gene immunosuppression. (D) FOXP3 stain of this biopsy. Note that the stain appears positive expression between years 1 and 2. How- (arrow) in approximately 10% of the infiltrating cells (approximately 50% CD4+ cells, not ever, these were populated with a differ- shown), possibly indicative of a less severe inflammatory component. Similar findings occur ent set of genes at each time (an example in the other Banff 1A biopsies (patients 3 and 4; Table 1). However, there are very few cells of which is shown in Supplemental Fig- to stain for FOXP3 in the tolerant recipients. H&E, hematoxylin and eosin. ure 1), consistent with significant differ- ences in immunosuppression protocols at those time points, as called for by the Figure 2A) and parallel CD8+ changes described.7 All of the above changes oc- weaning protocol. (not shown) persisted through 60 months curred independent of the tolerance ver- After 3 years post-transplantation, the post-transplantation. Increased percen- sus nontolerance designation. Other tolerant group remained off of immu- 2 tages of CD4+CD25highCD127 FOXP3+ PBMC immunophenotypic changes nosuppression, whereas the nontolerant cells (phenotypic regulatory T cells; Figure (CD14, CD56, CD25, CD3/CD16) were group was still on immunosuppression. 2B), some over 10 times pretransplant also indistinguishable (not shown). Therefore, we compared healthycontrols values (P=0.01), also persisted through In contrast, PBMC global gene ex- (no immunosuppression) with nonto- 60 months. CD19+ Bcellsreachedmore pression profiling and urinary quantita- lerant patients (immunosuppression), varied nadirs, but rebounded to pro- tive mRNA PCR correlated with toler- and subtracted differentially expressed longed higher levels than before trans- ance. PBMC global gene expression genes from this analysis from differen- plantation (P=0.01; Figure 2C). Parallel studies compared serial samples from tially expressed genes between healthy 2 increases in CD19+IgD/IgM+CD27 (na- five tolerant and four nontolerant pa- (no immunosuppression) and tolerant ïve) B cells also persisted through 60 tients (Figure 3A). Before transplanta- (no immunosuppression) patients, months post-transplantation (Figure tion, only 360 genes were differentially leaving a tolerance signature of 2169 2D), similar to but longer than recently expressed at relatively low levels and unique genes. Because some genes J Am Soc Nephrol 24: 1376–1385, 2013 HLA Identical Tolerance 1377 1378 BRIEF COMMUNICATION Table 1. Patient demographics and clinical courses in the first 10 renal transplant recipients in the HLA-identical DHSC tolerance protocol Maximum Journal of the American Society of Nephrology Latest Peak Preoperative Urine Latest Tx Microchimerism Patient Recipient Donor PRA Time Cr Current Time off Current Diagnosis Protein Biopsy in Year 1 Pre- Post-Tx (mg/ Daily of IS Microchimerism of Native per 24 Results Postoperativelyc
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