Repercusión de los shocks en los hogares

The long term success of renal transplantation depends on tricking the immune system into thinking that the kidney is not harmful, preferably by inducing tolerance. The role of B cells in transplant rejection and tolerance, but also in several autoimmune diseases has been increasingly appreciated. The wide use of anti-B-cell agents off ers accumulating evidence for their benefi cial eff ects in a wide range of diseases. Even though we have increased our knowledge about the role of B cells in renal transplantation, further research is needed. Currently, it is still diffi cult to predict whether anti-B-cell therapy will be benefi cial for the long term transplantation outcome or not. Also the mechanism of action of RTX may not be as straightforward as fi rst was expected. Although RTX depletes B cells, the precursors of antibody-producing cells, clinical experience with RTX in autoimmune diseases suggests that antibody levels are not always aff ected by RTX treatment. Altered T-cell stimulation by the B-cell pool, either by a change in antigen presentation or by the production of immunomodulatory cytokines might be important mechanisms of action of RTX as well. This would mean that the therapeutic eff ects go beyond simple B-cell depletion. In this thesis, we described that RTX can directly aff ect B-cell phenotype and function. Therefore, the eff ect of RTX on the immune response will not only be determined by the extent of B-cell depletion, but also by the functional properties of the remaining B cells. Moreover, the relative increase of regulatory B cells in the repopulating B-cell compartment after B-cell depletion might potentially promote tolerance. Eventually, the therapeutic eff ect of B-cell depletion will depend on the resulting balance between eff ector and regulatory B cells next to the timing of treatment and the type of disease or condition. Consequently, future therapy should be more directed at selective depletion or modulation of the B-cell compartment.

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References

1. Chapman JR, O’Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol. 2005;16(10):3015-26. 2. Billing H, Rieger S, Ovens J, et al.

Successful treatment of chronic

antibody-mediated rejection with

IVIG and rituximab in pediatric renal transplant recipients. Transplantation. 2008;86(9):1214-21.

3. Safi nia N, Afzali B, Atalar K, Lombardi G, Lechler RI. T-cell alloimmunity and chronic allograft dysfunction. Kidney International. 2010;78 Suppl 119:S2-12. 4. Kahan BD. Individuality: the barrier to

optimal immunosuppression. Nat Rev Immunol. 2003;3(10):831-8.

5. Zarkhin V, Chalasani G, Sarwal MM. The yin and yang of B cells in graft rejection and tolerance. TransplantRev(Orlando). 2010;24(2):67-78

6. Hippen BE, DeMattos A, Cook WJ,

Kew CE, Gaston RS. Association of CD20+ infi ltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. AmJTransplant. 2005;5(9):2248-52.

7. Zarkhin V, Kambham N, Li L, et al. Characterization of intra-graft B cells during renal allograft rejection. Kidney International. 2008;74(5):664-73.

8. Otten HG, Verhaar MC, Borst HP, Hene

RJ, van Zuilen AD. Pretransplant donor- specifi c HLA class-I and -II antibodies are associated with an increased risk for kidney graft failure. Am J Transplant. 2012;12(6):1618-23.

9. Newell KA, Asare A, Kirk AD, et al. Identifi cation of a B cell signature

associated with renal transplant

tolerance in humans. JClinInvest.

2010;120(6):1836-47.

10. Tyden G, Ekberg H, Tufveson G, Mjornstedt L. A randomized, double- blind, placebo-controlled study of single dose rituximab as induction in renal transplantation: a 3-year follow-up. Transplantation. 2012;94(3):e21-2. 11. Kamar N, Milioto O, Puissant-Lubrano B,

et al. Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients. AmJTransplant. 2010;10(1):89-98. 12. Stegall MD, Raghavaiah S, Gloor JM.

The (re)emergence of B cells in organ

transplantation. CurrOpinOrgan

Transplant. 2010;15(4):451-5.

13. Zarkhin V, Lovelace PA, Li L, Hsieh SC, Sarwal MM. Phenotypic evaluation of B-cell subsets after rituximab for treatment of acute renal allograft

rejection in pediatric recipients.

Transplantation. 2011;91(9):1010-8. 14. Lanio N, Sarmiento E, Gallego A, et

al. Alterations of naive and memory B-cell subsets are associated with risk of rejection and infection in heart recipients. Transpl Int. 2013;26(8):800- 12.

15. Ramos EJ, Pollinger HS, Stegall MD, Gloor JM, Dogan A, Grande JP. The eff ect of desensitization protocols on human splenic B-cell populations in vivo. AmJTransplant. 2007;7(2):402-7. 16. Leandro MJ. B-cell subpopulations

in humans and their diff erential

susceptibility to depletion with anti- CD20 monoclonal antibodies. Arthritis Res Ther. 2013;15 Suppl 1:S3.

17. Roll P, Palanichamy A, Kneitz C, Dorner T, Tony HP. Regeneration of B cell subsets

after transient B cell depletion using anti- CD20 antibodies in rheumatoid arthritis. Arthritis Rheum. 2006;54(8):2377-86. 18. Genberg H, Hansson A, Wernerson A,

Wennberg L, Tyden G. Pharmacodynamics of rituximab in kidney allotransplantation. AmJTransplant. 2006;6(10):2418-28. 19. Sidner RA, Book BK, Agarwal A, Bearden

CM, Vieira CA, Pescovitz MD. In vivo human B-cell subset recovery after in vivo depletion with rituximab, anti- human CD20 monoclonal antibody. Human Antibodies. 2004;13(3):55-62. 20. Fehr T, Rusi B, Fischer A, Hopfer H,

Wuthrich RP, Gaspert A. Rituximab and intravenous immunoglobulin treatment of chronic antibody-mediated kidney allograft rejection. Transplantation. 2009;87(12):1837-41.

21. Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly

HLA-sensitized patients awaiting

kidney transplantation. Transplantation. 2010;89(9):1095-102.

22. Kopchaliiska D, Zachary AA, Montgomery RA, Leff ell MS. Reconstitution of peripheral allospecifi c CD19+ B-cell subsets after B-lymphocyte depletion therapy in renal transplant patients. Transplantation. 2009;87(9):1394-401. 23. Blair PA, Norena LY, Flores-Borja F, et al.

CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010;32(1):129-40.

24. Fuchs EJ, Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992;258(5085):1156-9.

25. Reichardt P, Dornbach B, Rong S, et al. Naive B cells generate regulatory T cells

in the presence of a mature immunologic synapse. Blood. 2007;110(5):1519-29. 26. Anolik JH, Barnard J, Owen T, et al.

Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis Rheum. 2007;56(9):3044-56.

27. Roll P, Dorner T, Tony HP. Anti-CD20 therapy in patients with rheumatoid

arthritis: predictors of response

and B cell subset regeneration after repeated treatment. Arthritis Rheum. 2008;58(6):1566-75.

28. Heidt S, Roelen DL, Eijsink C, van Kooten C, Claas FH, Mulder A. Eff ects of immunosuppressive drugs on purifi ed human B cells: evidence supporting the use of MMF and rapamycin. Transplantation. 2008;86(9):1292-300. 29. Hanson RG, Peters MG, Hoofnagle JH.

Eff ects of immunosuppressive therapy with prednisolone on B and T lymphocyte function in patients with chronic type B hepatitis. Hepatology. 1986;6(2):173-9. 30. Cupps TR, Gerrard TL, Falkoff RJ,

Whalen G, Fauci AS. Eff ects of in vitro corticosteroids on B cell activation, proliferation, and diff erentiation. J Clin Invest. 1985;75(2):754-61.

31. Addo MM, Rosenberg ES. Cellular immune responses in transplantation- associated chronic viral infections. Transplant infectious disease : an offi cial journal of the Transplantation Society. 2002;4(1):31-40.

32. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion

with rituximab in patients with

rheumatoid arthritis. Arthritis Rheum. 2006;54(2):613-20.

7

33. Roll P, Palanichamy A, Kneitz C, Dorner T, Tony HP. Regeneration of B cell subsets after transient B cell depletion using anti- CD20 antibodies in rheumatoid arthritis. Arthritis Rheum. 2006;54(8):2377-86. 34. Liu C, Noorchashm H, Sutter JA, et al.

B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat Med. 2007;13(11):1295-8.

35. Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest. 2008;118(10):3420-30. 36. Duddy ME, Alter A, Bar-Or A. Distinct

profi les of human B cell eff ector cytokines: a role in immune regulation? JImmunol. 2004;172(6):3422-7.

37. Harris DP, Haynes L, Sayles PC, et al.

Reciprocal regulation of polarized

cytokine production by eff ector B and T cells. NatImmunol. 2000;1(6):475-82. 38. Janeway CA, Jr., Ron J, Katz ME. The B

cell is the initiating antigen-presenting cell in peripheral lymph nodes. JImmunol. 1987;138(4):1051-5.

39. Iwata S, Saito K, Tokunaga M, et al. Phenotypic changes of lymphocytes

in patients with systemic lupus

erythematosus who are in longterm remission after B cell depletion therapy with rituximab. Journal of Rheumatology. 2011;38(4):633-41.

40. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008;112(4):1147-50.

41. Bar-Or A, Fawaz L, Fan B, et al. Abnormal B-cell cytokine responses a trigger of

T-cell-mediated disease in MS? Annals of Neurology. 2010;67(4):452-61.

42. Nakou M, Sidiropoulos P, Bertsias G, et al. Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells

correlates with clinical response.

Arthritis ResTher. 2009;11(4):R131. 43. Vos K, Thurlings RM, Wijbrandts CA, van

SD, Gerlag DM, Tak PP. Early eff ects of rituximab on the synovial cell infi ltrate in patients with rheumatoid arthritis. Arthritis Rheum. 2007;56(3):772-8.

44. Bowles JA, Weiner GJ. CD16

polymorphisms and NK activation

induced by monoclonal antibody-coated target cells. Journal of Immunological Methods. 2005;304(1-2):88-99. 45. Thaunat O, Patey N, Gautreau C, et

al. B cell survival in intragraft tertiary lymphoid organs after rituximab therapy. Transplantation. 2008;85(11):1648-53. 46. Tay SS, Plain KM, Bishop GA. Role of

IL-4 and Th2 responses in allograft rejection and tolerance. CurrOpinOrgan Transplant. 2009;14(1):16-22.

47. Carpenter EL, Mick R, Rech AJ, et al. Collapse of the CD27+ B-cell compartment associated with systemic plasmacytosis in patients with advanced melanoma and other cancers. Clinical Cancer Research. 2009;15(13):4277-87. 48. Edwards JCW, Cambridge G. B-cell

targeting in rheumatoid arthritis and other autoimmune diseases. Nature Reviews Immunology. 2006;6(5):394- 403.

49. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high

lymphocyte counts after treatment with an anti-CD20 monoclonal antibody

(rituximab, IDEC-C2B8). Blood.