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Yvonne Suessmuth, PhD Postdoctoral Fellow Emory Transplant Center, Atlanta, GA

The 12 th Joint Annual Congress of the American Society of Transplant Surgeons and The American Society of Transplantation. Yvonne Suessmuth, PhD Postdoctoral Fellow Emory Transplant Center, Atlanta, GA.

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Yvonne Suessmuth, PhD Postdoctoral Fellow Emory Transplant Center, Atlanta, GA

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  1. The 12th Joint Annual Congress of the American Society of Transplant Surgeons and The American Society of Transplantation Yvonne Suessmuth, PhDPostdoctoral FellowEmory Transplant Center, Atlanta, GA I have no financial relationships to disclose within the past 12 months relevant to my presentation My presentationdoes not include discussion of off-label or investigational use I do not intend to reference unlabeled/unapproved uses of drugs or products in my presentation.

  2. Comparison of Viral Immunity in Stable Renal Allograft Recipients Treated with Belataceptor Tacrolimus Emory Transplant Center Yvonne Suessmuth PhD, PW Thompson; C Breeden; B Johnson; R Jones; LA Stempora; J Cheeseman; J Joseph; B Begley; S Thomas; AD Kirk; K Newell; CP Larsen; AK Mehta Emory Transplant Center

  3. Belatacept • Newly approved high-affinity CTLA4Ig variant • Blocks interaction of CD28 with CD80/86 • Inhibits T cell proliferation and differentiation • Improved GFR in belatacept groups vs. CSA • Improved metabolic control • Increased incidence of EBV related PTLD • Very little data on impact of belatacept on protective immunity X X Larsen et al. Am J Transplant 2006; 6: 876 – 883.

  4. In vitro treatment of PBMCs with Belatacept does not inhibit EBV specific memory Mehta AK, et al. ATC 2011

  5. In vitro treatment of PBMCs with Belatacept does not inhibit EBV specific memory • Lack of data on viral specific protective immunity in patients treated with belatacept Mehta AK, et al. ATC 2011

  6. Study Design and Patient populations • Subjects were enrolled from existing immune monitoring protocols at Emory University • Peripheral blood samples were collected at a single timepoint • Phenotypic and functional analysis of peripheral blood lymphocytes were performed using rationally-designed and validated flow cytometric panel • 10 healthy volunteers • 10 transplant recipients (>6mos s/p renal allograft) on stable dose of Belatacept, MMF, and prednisone • 10 transplant recipients (>6mos s/p renal allograft) on stable dose of Tacrolimus, MMF, and prednisone

  7. Subject Characteristics

  8. Subject Characteristics

  9. Methods • PBMCs were rested 8h in 10% RPMI, then stimulated for 12h with either: • CMV pp65 PepMix = 15-mers overlapping by 11 aa covering the length of pp65 • EBV BZLF PepMix = 15-mers overlapping by 11 aa covering the length of BZLF • EBV Peptide pool = Peptides from several EBV proteins but restricted by HLA types • Cells were then stained for the following markers:

  10. Methods • PBMCs were rested 8h in 10% RPMI, then stimulated for 12h with either: • CMV pp65 PepMix = 15-mers overlapping by 11 aa covering the length of pp65 • EBV BZLF PepMix = 15-mers overlapping by 11 aa covering the length of BZLF • EBV Peptide pool = Peptides from several EBV proteins but restricted by HLA types • Cells were then stained for the following markers:

  11. Gating Strategy Live CD3 cells Lymphocytes Singlets

  12. Gating Strategy Live CD3 cells Lymphocytes Singlets CD4 vs CD8 cells

  13. Gating Strategy Live CD3 cells Lymphocytes Singlets CD4 vs CD8 cells

  14. Belatacept treated patients show no difference in TNFα/IFNγ production in CD4 cells compared to Tacrolimus Belatacept patient CD4 EBV stimulated

  15. Belatacept treated patients show no difference in TNFα/IFNγ production in CD8 cells compared to Tacrolimus Belatacept patient CD8 EBV stimulated Belatacept patient CD8 CMV stimulated

  16. Belatacept treated patients show no difference in TNFα/IFNγ production in CD8 cells compared to Tacrolimus Belatacept patient CD8 EBV stimulated Belatacept patient CD8 CMV stimulated

  17. Belatacept patients show more TNFα/IFNγ production in Central Memory cells but lower in Naïve CD8 cells in response to EBV stimulation p= 0.028 p= 0.054 Naive TCM TEMRA CCR7 TEM CD45RA

  18. Belatacept patients show more TNFα/IFNγ production in Central Memory cells but lower in Naïve CD8 cells in response to EBV stimulation p= 0.028 p= 0.054 Naive TCM TEMRA CCR7 TEM CD45RA

  19. Belatacept patients show more TNFα/IFNγ production in Central Memory cells but lower in Naïve CD8 cells in response to EBV stimulation p= 0.028 p= 0.054 Naive TCM TEMRA CCR7 TEM CD45RA

  20. Belatacept patients show more TNFα/IFNγ production in Central Memory cells but lower in Naïve CD8 cells in response to EBV stimulation p= 0.028 p= 0.054 Naive TCM TEMRA CCR7 TEM CD45RA

  21. In response to CMV stimulation Tacrolimus treated patients show higher production of TNFα/IFNγ in all CD8 Memory subsets p=0.009 Naive TCM TEMRA CCR7 TEM CD45RA

  22. Belatacept treated patients show a robust trend towards increased CD27lo/CD28lo cells Healthy Belatacept Tacrolimus

  23. Belatacept treated patients show a robust trend towards increased CD27lo/CD28lo cells Healthy Belatacept Tacrolimus

  24. Belatacept treated patients show a robust trend towards increased CD27lo/CD28lo cells Healthy Belatacept Tacrolimus

  25. Increased CD27lo/CD28lo cell numbers in Belatacept patients do not correlate with increased TNFα/IFNγ double producing cells in this population EBV CMV

  26. Increased CD27lo/CD28lo cell numbers in Belatacept patients do not correlate with increased TNFα/IFNγ double producing cells in this population EBV CMV

  27. Increased CD27lo/CD28lo cell numbers in Belatacept patients do not correlate with increased TNFα/IFNγ double producing cells in this population EBV CMV

  28. Conclusions • Belatacept treatment does not appear to significantly impact virus-specific immune function as compared to Tacrolimus treatment. • Differences in TNFα/IFNγ production are possibly due to the difference in cohorts but need further investigation • Differences observed between healthy controls and treated patients in memory subsets suggest that immunosuppressive agents influence how viral-specific memory is maintained • Increased numbers of late differentiated cells (CD27lo/CD28lo) in Belatacept patients do not coincide with significantly decreased viral- specific immunity in these patients.

  29. Future Plans • Enroll further 10 early post transplant Belatacept and 10 late post transplant Tacrolimus treated patients to ensure better comparison between the groups. • Monitor patients longitudinally in the CTOT10 Trial comparing long-term treatment with Belatacept to Tacrolimus

  30. Acknowledgments Special Thanks To: • Christian P Larsen • Aneesh K Mehta • Allan D Kirk • Kenneth Newell • Peter Thompson • Linda Stempora • Cindy Breeden • Brandi Johnson • He Xu ETC Biorepository • Rachelle Jones • Stephanie Monday • Kendra Bryant • Jennifer Cheeseman ETC Clinical Research Coordinators • Elizabeth Begley • Shine Thomas • Elizabeth Ferry The Patients! Grant support: A portion of this work was performed as part of the Clinical Trials in Organ Transplantation, supported by the National Institute of Allergy and Infectious Diseases.

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