Blood Gene Expression Profiling in a Randomized Controlled Trial of rATG Vs. IL2RA Induction Reveals the Differences in Immune Impact and Mechanisms

K. Chavin,¹ D. Taber,¹ S. Kurian,² T. Gelbart,² N. Pilch,¹ S. Nadig,¹ J. McGillicuddy,¹ T. Srinivas,¹ C. Bratton,¹ P. Baliga,¹ D. Salomon.²

¹MUSC, Charleston, SC
²Scripps Research Institute, La Jolla, CA.

Meeting: 2015 American Transplant Congress

Abstract number: 433

Keywords: African-American, Gene expression, Induction therapy, Kidney transplantation

Session Information

Session Name: Concurrent Session: Immune Monitoring II

Session Type: Concurrent Session

Date: Tuesday, May 5, 2015

Session Time: 4:00pm-5:30pm

Presentation Time: 4:00pm-4:12pm

Location: Terrace IV

We performed global gene expression profiling using microarrays on samples from a prospective, RCT designed to study the safety & efficacy of induction with antithymocyte globulin (rATG) vs. IL2RA. The purpose was to identify molecular mechanisms and predictive signatures that reflect the differences and impact of these two therapies on graft function and rejection.

Methods: Single center, open labeled RCT study. 200 patients (n=98; IL2RA and n=102; ATG) enrolled. Patients were randomized for induction in combo with FK, MMF and steroids; stratified by race, re-transplant, PRA>20% & CIT>24hrs. A total of 181 blood samples from 91 patients (67 pre-perfusion, 72 6-wk protocol & 22 “for cause”) were profiled using Affymetrix HT 133 PM Plus Arrays. All class comparisons were done using a one-way ANOVA model in Partek Genomics Suite. We used the Nearest Centroid (NC) algorithm to build predictive models. Pathway analyses were done using Ingenuity Pathway Analysis.

Results: BPAR rates by 1 yr were significantly lower with rATG vs IL2RA (2% vs. 7%, p=0.03); eGFRs at 1 yr were not different (56 vs. 57 ml/min). Microarray analysis of 6-wk protocol samples revealed the molecular differences in the immune impact of IL2RA vs rATG. ATG's protective impact is dramatically greater for Caucasians (C) vs African Americans (AA); 4x more genes downregulated after induction in C. Of 2197 shared genes for AA vs. C, 70% were actually upregulated after induction in AA subjects. Pathways more effectively suppressed by rATG vs IL2RA mapped to CD28, PPAR, EIF2, mTOR, TCR, BCR and iCOS-iCOSL signaling. Using 6-wk profiles, we discovered rATG & IL2RA-specific signatures predicting clinical AR risk in the 1st yr postTx (n=16 AR; AUC∼90%). Finally, 6-wk signatures also specific to the therapies predicted 12-mo graft function (eGFR >60 vs. <60).

Conclusions: Clinically, rATG induction may provide better protection against rejection in AA recipients. But molecular profiling tells a different story of much less effective induction immunosuppression and the specific immune pathways involved. We believe that despite a short term benefit, current use of rATG induction for AA is far from optimal immunosuppression & this raises concerns for an impact on longterm outcomes. We also identified therapy-specific signatures predictive for AR risk and 1-yr graft function.

To cite this abstract in AMA style:

Chavin K, Taber D, Kurian S, Gelbart T, Pilch N, Nadig S, McGillicuddy J, Srinivas T, Bratton C, Baliga P, Salomon D. Blood Gene Expression Profiling in a Randomized Controlled Trial of rATG Vs. IL2RA Induction Reveals the Differences in Immune Impact and Mechanisms [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/blood-gene-expression-profiling-in-a-randomized-controlled-trial-of-ratg-vs-il2ra-induction-reveals-the-differences-in-immune-impact-and-mechanisms/. Accessed December 3, 2024.

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