Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig

American Journal of Transplantation

Volumn 16, Issue 9, 2016, Pages 2612-2623

  Oh, B ^a   Yoon, J ^b   Farris, A ^c   Kirk, A ^a,b   Knechtle, S ^a,b   Kwun, J ^a,b  

^a EMORY UNIVERSITY   (United States)

^b DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

alloantibody; basic (laboratory) research science; heart transplantation cardiology; immunobiology; immunosuppression immune modulation; immunosuppressive regimens; induction; rejection: antibody mediated (ABMR); T cell biology

Indexed keywords

ALEMTUZUMAB; ALLOANTIBODY; DONOR SPECIFIC ANTIBODY; RAPAMYCIN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIBODY MEDIATED REJECTION; ANTIBODY PRODUCTION; ARTICLE; CARDIAC ALLOGRAFT VASCULOPATHY; CARDIAC GRAFT REJECTION; GRAFT DYSFUNCTION; GRAFT RECIPIENT; HEART TRANSPLANTATION; HELPER CELL; HISTOLOGY; HOMEOSTASIS; HUMORAL IMMUNITY; IMMUNOHISTOCHEMISTRY; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATORY INFILTRATE; KIDNEY GRAFT REJECTION; MAJOR HISTOCOMPATIBILITY COMPLEX; MOUSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; T CELL DEPLETION; VASCULAR DISEASE;

EID: 84984607313     PISSN: 16006135     EISSN: 16006143     Source Type: Journal    
DOI: 10.1111/ajt.13789     Document Type: Article

References (46)

1. Cao W, Manicassamy S, Tang H, et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 2008; 9: 1157–1164.
2. Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 2008; 105: 7797–7802.
3. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009; 9: 324–337.
4. Budde K, Becker T, Arns W, et al.; Investigators ZS. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: An open-label, randomised, controlled trial. Lancet 2011; 377: 837–847.
5. Lebranchu Y, Thierry A, Toupance O, et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: Concept study. Am J Transplant 2009; 9: 1115–1123.
6. Guba M, Pratschke J, Hugo C, et al.; Group SM-S. Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: One-year analysis of a randomized multicenter trial. Transplantation 2010; 90: 175–183.
7. Weir MR, Mulgaonkar S, Chan L, et al. Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: A randomized, controlled Spare-the-Nephron trial. Kidney Int 2011; 79: 897–907.
8. Lefaucheur C, Nochy D, Hill GS, et al. Determinants of poor graft outcome in patients with antibody-mediated acute rejection. Am J Transplant 2007; 7: 832–841.
9. Gloor J, Cosio F, Lager DJ, Stegall MD. The spectrum of antibody-mediated renal allograft injury: Implications for treatment. Am J Transplant 2008; 8: 1367–1373.
10. Everly MJ, Everly JJ, Arend LJ, et al. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am J Transplant 2009; 9: 1063–1071.
11. Loupy A, Suberbielle-Boissel C, Hill GS, et al. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am J Transplant 2009; 9: 2561–2570.
12. Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol 2010; 21: 1398–1406.
13. Gloor JM, Sethi S, Stegall MD, et al. Transplant glomerulopathy: Subclinical incidence and association with alloantibody. Am J Transplant 2007; 7: 2124–2132.
14. Cosio FG, Gloor JM, Sethi S, Stegall MD. Transplant glomerulopathy. Am J Transplant 2008; 8: 492–496.
15. Sis B, Mengel M, Haas M, et al. Banff ‘09 meeting report: Antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 2010; 10: 464–471.
16. Aagaard-Tillery KM, Jelinek DF. Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin. Cell Immunol 1994; 156: 493–507.
17. Donahue AC, Fruman DA. Distinct signaling mechanisms activate the target of rapamycin in response to different B-cell stimuli. Eur J Immunol 2007; 37: 2923–2936.
18. Sakata A, Kuwahara K, Ohmura T, Inui S, Sakaguchi N. Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro. Immunol Lett 1999; 68: 301–309.
19. Heidt S, Roelen DL, Eijsink C, van Kooten C, Claas FH, Mulder A. Effects of immunosuppressive drugs on purified human B cells: Evidence supporting the use of MMF and rapamycin. Transplantation 2008; 86: 1292–1300.
20. Knechtle SJ, Pirsch JD, Fechner JH, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: Results of a pilot study. Am J Transplant 2003; 3: 722–730.
21. Kwun J, Oh BC, Gibby AC, et al. Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment. Am J Transplant 2012; 12: 2641–2651.
22. Kwun J, Hu H, Schadde E, et al. Altered distribution of H60 minor H antigen-specific CD8 T cells and attenuated chronic vasculopathy in minor histocompatibility antigen mismatched heart transplantation in Cxcr3-/- mouse recipients. J Immunol 2007; 179: 8016–8025.
23. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005; 24: 1710–1720.
24. Taylor JJ, Pape KA, Jenkins MK. A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med 2012; 209: 597–606.
25. Kaji T, Ishige A, Hikida M, et al. Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. J Exp Med 2012; 209: 2079–2097.
26. Chen J, Yin H, Xu J, et al. Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. Am J Transplant 2013; 13: 2280–2292.
27. Kim EJ, Kwun J, Gibby AC, et al. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant 2014; 14: 59–69.
28. Masetti M, Potena L, Nardozza M, et al. Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice. Am J Transplant 2013; 13: 1217–1226.
29. Liefeldt L, Brakemeier S, Glander P, et al. Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation. Am J Transplant 2012; 12: 1192–1198.
30. Knechtle SJ, Pascual J, Bloom DD, et al. Early and limited use of tacrolimus to avoid rejection in an alemtuzumab and sirolimus regimen for kidney transplantation: Clinical results and immune monitoring. Am J Transplant 2009; 9: 1087–1098.
31. Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 2008; 111: 453–462.
32. Bensinger SJ, Walsh PT, Zhang J, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 2004; 172: 5287–5296.
33. Wang Y, Camirand G, Lin Y, et al. Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. J Immunol 2011; 186: 2809–2818.
34. Procaccini C, De Rosa V, Galgani M, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 2010; 33: 929–941.
35. Wing JB, Sakaguchi S. Foxp3(+) T(reg) cells in humoral immunity. Int Immunol 2014; 26: 61–69.
36. Linterman MA, Pierson W, Lee SK, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 2011; 17: 975–982.
37. Morgan ME, Sutmuller RP, Witteveen HJ, et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum 2003; 48: 1452–1460.
38. Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG. B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2001; 2: 1126–1132.
39. Sucher R, Fischler K, Oberhuber R, et al. IDO and regulatory T cell support are critical for cytotoxic T lymphocyte-associated Ag-4 Ig-mediated long-term solid organ allograft survival. J Immunol 2012; 188: 37–46.
40. Badell IR, Russell MC, Cardona K, et al. CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8. Am J Transplant 2012; 12: 1918–1923.
41. Chavez H, Beaudreuil S, Abbed K, et al. Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade. Transpl Immunol 2007; 17: 243–248.
42. Kirk AD, Guasch A, Xu H, et al. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant 2014; 14: 1142–1151.
43. Burghuber CK, Kwun J, Page EJ, et al. Antibody-mediated rejection in sensitized nonhuman primates: Modeling human biology. Am J Transplant 2016; doi: 10.1111/ajt.13688.
44. Kwun J, Page E, Hong JJ, et al. Neutralizing BAFF/APRIL with atacicept prevents early DSA formation and AMR development in T cell depletion induced nonhuman primate AMR model. Am J Transplant 2015; 15: 815–822.
45. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation 2003; 76: 120–129.
46. Taylor DK, Neujahr D, Turka LA. Heterologous immunity and homeostatic proliferation as barriers to tolerance. Curr Opin Immunol 2004; 16: 558–564.