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The Immunomodulating Effects of Thalidomide and Dexamethasone in a Murine Cardiac Allograft Transplantation Model

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Purpose: The immunomodulatory effects of thalidomide (TM) and dexamethasone (DX) on immune cells and their co-stimulatory,co-inhibitory molecules in vitro and in vivo have been previously reported. The current study investigated the effects of TMand the combinatorial treatment with DX on immune cells using a murine cardiac allograft transplantation model. Materials and Methods: Intraabdominal transplant of cardiac allografts from BALB/c (H-2d) donors to C57BL/6 (H-2b) recipientswas performed. After transplantation, mice were injected daily with TM or DX or a combination of both TM and DX (TM/DX) by intraperitonealroute until the time of graft loss. CD4+ T cell subsets and CD11c+ cells in the peripheral blood mononuclear cells andspleen were examined and quantified with flow cytometry. Serum IL-6 levels were measured by enzyme-linked immunosorbent assayon day 7. Results: The mean graft survivals were 6.86 days in the untreated group, and 10.0 days in the TM/DX group (p<0.001). The TM/DXtreatment affected the CD4+ T cell subsets without suppressing the total CD4+ T cell population. The CD4+FOXP3+/CD4+CD44hi Tcell ratio increased. Increase in cell counts and median fluorescence intensity on CD11c+CD85k+ with TM/DX were observed. Theinhibition of pro-inflammatory cytokine interleukin-6 was also observed. Conclusion: These outcomes suggest the immunomodulating effect of the TM/DX combinatorial treatment. In conclusion, TM/DX combination may be a promising immunomodulatory approach for preventing allograft rejection and improving graft survivalby inducing tolerance in transplantation.

Abstract

Purpose: The immunomodulatory effects of thalidomide (TM) and dexamethasone (DX) on immune cells and their co-stimulatory,co-inhibitory molecules in vitro and in vivo have been previously reported. The current study investigated the effects of TMand the combinatorial treatment with DX on immune cells using a murine cardiac allograft transplantation model. Materials and Methods: Intraabdominal transplant of cardiac allografts from BALB/c (H-2d) donors to C57BL/6 (H-2b) recipientswas performed. After transplantation, mice were injected daily with TM or DX or a combination of both TM and DX (TM/DX) by intraperitonealroute until the time of graft loss. CD4+ T cell subsets and CD11c+ cells in the peripheral blood mononuclear cells andspleen were examined and quantified with flow cytometry. Serum IL-6 levels were measured by enzyme-linked immunosorbent assayon day 7. Results: The mean graft survivals were 6.86 days in the untreated group, and 10.0 days in the TM/DX group (p<0.001). The TM/DXtreatment affected the CD4+ T cell subsets without suppressing the total CD4+ T cell population. The CD4+FOXP3+/CD4+CD44hi Tcell ratio increased. Increase in cell counts and median fluorescence intensity on CD11c+CD85k+ with TM/DX were observed. Theinhibition of pro-inflammatory cytokine interleukin-6 was also observed. Conclusion: These outcomes suggest the immunomodulating effect of the TM/DX combinatorial treatment. In conclusion, TM/DX combination may be a promising immunomodulatory approach for preventing allograft rejection and improving graft survivalby inducing tolerance in transplantation.

참고문헌 (40)

  1. Taylor AL, "Immunosuppressive agents in solid organ transplantation : mechanisms of action and therapeutic efficacy", Crit Rev Oncol Hematol, 56, pp.23~46 (2005)
  2. Halloran PF, "Immunosuppressive drugs for kidney transplantation", N Engl J Med, 351, pp.2715~2729 (2004)
  3. Ojo AO, "Chronic renal failure after transplantation of a nonrenal organ", N Engl J Med, 349, pp.931~940 (2003)
  4. Romano M, "Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity", Front Immunol, 10, pp.43~ (2019)
  5. Franks ME, "Thalidomide", Lancet, 363, pp.1802~1811 (2004)
  6. Okafor MC, "Thalidomide for erythema nodosum leprosum and other applications", Pharmacotherapy, 23, pp.481~493 (2003)
  7. Sheskin J, "Thalidomide in the treatment of lepra reactions", Clin Pharmacol Ther, 6, pp.303~306 (1965)
  8. Sherbet GV, "Therapeutic potential of thalidomide and its analogues in the treatment of cancer", Anticancer Res, 35, pp.5767~5772 (2015)
  9. Pitzalis C, "Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion : an additional mechanism for their anti-inflammatory and immunosuppressive effect", J Immunol, 158, pp.5007~5016 (1997)
  10. Chauhan D, "Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B", Blood, 87, pp.1104~1112 (1996)
  11. Chan ED, "Use of glucocorticoids in the critical care setting : science and clinical evidence", Pharmacol Ther, 206, pp.107428~ (2020)
  12. Franchimont D, "Overview of the actions of glucocorticoids on the immune response : a good model to characterize new pathways of immunosuppression for new treatment strategies", Ann N Y Acad Sci, 1024, pp.124~137 (2004)
  13. Oray M, "Longterm side effects of glucocorticoids", Expert Opin Drug Saf, 15, pp.457~465 (2016)
  14. Reske A, "Complications of immunosuppressive agents therapy in transplant patients", Minerva Anestesiol, 81, pp.1244~1261 (2015)
  15. Longui CA, "Glucocorticoid therapy : minimizing side effects", J Pediatr(Rio J), 83, pp.S163~77 (2007)
  16. Zamagni E, "Long-term results of thalidomide and dexamethasone(thaldex)as therapy of first relapse in multiple myeloma", Ann Hematol, 91, pp.419~426 (2012)
  17. Rajkumar SV, "Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma", J Clin Oncol, 20, pp.4319~4323 (2002)
  18. Lee SW, "Attenuation of nephritis in lupus-prone mice by thalidomide", Rheumatology(Oxford), 51, pp.2131~2140 (2012)
  19. Wood KJ, "Regulatory immune cells in transplantation", Nat Rev Immunol, 12, pp.417~430 (2012)
  20. Josefowicz SZ, "Control of regulatory T cell lineage commitment and maintenance", Immunity, 30, pp.616~625 (2009)
  21. Zheng XX, "The balance of deletion and regulation in allograft tolerance", Immunol Rev, 196, pp.75~84 (2003)
  22. Krystufkova E, "Regulatory T cells in kidney transplant recipients : the effect of induction immunosuppression therapy", Nephrol Dial Transplant, 27, pp.2576~2582 (2012)
  23. Dummer CD, "FOXP3+ regulatory T cells : from suppression of rejection to induction of renal allograft tolerance", Transpl Immunol, 26, pp.1~10 (2012)
  24. Pearson RM, "In vivo reprogramming of immune cells : technologies for induction of antigen-specific tolerance", Adv Drug Deliv Rev, 114, pp.240~255 (2017)
  25. Steinman RM, "Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice", Proc Natl Acad Sci U S A, 75, pp.5132~5136 (1978)
  26. Banchereau J, "Dendritic cells and the control of immunity", Nature, 392, pp.245~252 (1998)
  27. Morelli AE, "Tolerogenic dendritic cells and the quest for transplant tolerance", Nat Rev Immunol, 7, pp.610~621 (2007)
  28. Kim BS, "Role of thalidomide on the expression of OX40, 4-1BB, and GITR in T cell subsets", Transplant Proc, 48, pp.1270~1274 (2016)
  29. Kim EJ, "Enhanced immune-modulatory effects of thalidomide and dexamethasone co-treatment on T cell subsets", Immunology, 152, pp.628~637 (2017)
  30. Kim BS, "Immune modulatory effect of thalidomide on T cells", Transplant Proc, 47, pp.787~790 (2015)
  31. 김은지, "Systemic Immunomodulatory Effects of Combinatorial Treatment of Thalidomide and Dexamethasone on T Cells and Other Immune Cells", Yonsei Medical Journal, 62(2), pp.137~148 (2021), 연세대학교의과대학[DOI]
  32. Niimi M, "The technique for heterotopic cardiac transplantation in mice : experience of 3000 operations by one surgeon", J Heart Lung Transplant, 20, pp.1123~1128 (2001)
  33. Manavalan JS, "High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells", Transpl Immunol, 11, pp.245~258 (2003)
  34. Maldonado RA, "How tolerogenic dendritic cells induce regulatory T cells", Adv Immunol, 108, pp.111~165 (2010)
  35. Manicassamy S, "Dendritic cell control of tolerogenic responses", Immunol Rev, 241, pp.206~227 (2011)
  36. Jordan SC, "Interleukin-6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection : therapeutic implications of IL-6 receptor blockade", Transplantation, 101, pp.32~44 (2017)
  37. Liang Y, "Graft produced interleukin-6 functions as a danger signal and promotes rejection after transplantation", Transplantation, 84, pp.771~777 (2007)
  38. Schäcke H, "Mechanisms involved in the side effects of glucocorticoids", Pharmacol Ther, 96, pp.23~43 (2002)
  39. Prelovsek O, "High dexamethasone concentration prevents stimulatory effects of TNF-alpha and LPS on IL-6 secretion from the precursors of human muscle regeneration", Am J Physiol Regul Integr Comp Physiol, 291, pp.R1651~ (2006)[DOI]
  40. Jiskoot W, "Mouse models for assessing protein immunogenicity : lessons and challenges", J Pharm Sci, 105, pp.1567~1575 (2016)

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