sdü tıp fak derg Medical Journal of Süleyman Demirel University 2602-2109 Süleyman Demirel Üniversitesi 10.17343/sdutfd.561701 Clinical Sciences Klinik Tıp Bilimleri Cell Therapies in Kidney Transplantation Böbrek Naklinde Hücresel Tedavilerin Kullanımı https://orcid.org/0000-0002-1062-3290 Şenol Özgür EGE ÜNİVERSİTESİ, FEN BİLİMLERİ ENSTİTÜSÜ, BİYOTEKNOLOJİ ANABİLİM DALI (DİSİPLİNLERARASI) https://orcid.org/0000-0003-0466-7294 Kaya Egemen MUĞLA SITKI KOÇMAN ÜNİVERSİTESİ, TIP FAKÜLTESİ, TEMEL TIP BİLİMLERİ BÖLÜMÜ, FİZYOLOJİ ANABİLİM DALI https://orcid.org/0000-0001-9178-2850 Karakuş Volkan MUĞLA T.C. SB. MUĞLA SITKI KOÇMAN ÜNİVERSİTESİ EĞİTİM VE ARAŞTIRMA HASTANESİ 09 01 2020 27 3 413 420 05 08 2019 06 24 2019 Copyright © 1994, Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi 1994 Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi

Atthe present time, with the development of medicine, surgery and the use oftechnologically advanced modern drugs, many diseases, including kidneydiseases, have become treatable. Kidneytransplantation has become a treatment option for kidney diseases and kidneytransplant rates have increased as well as life expectancy has been prolongedby means of obtained success. Immunosuppressive drugs are used in theposttransplant treatment process of renal transplant patients. With the newtreatment options, it is aimed to increase the success rate of kidneytransplantation and also to eliminate the side effects which are caused by theuse of immunosuppressive drugs. Cellular therapies are one of the treatmentoptions that are studied for use in kidney transplantation. Regulator T cells,regulator B cells, regulator macrophages, dendritic cells, mesenchymal stemcells are cell sources that are searched and experimented for use in organtransplantation. It has been shown that successful results have been obtainedby using cell therapies in studies carried out with experimental animal modelsfor transplantation. In this review, cell therapies used in and candidatefor renal transplantation are discussed.

Günümüzde,tıp, cerrahi alanında görülen gelişmeler ve teknolojik olarak geliştirilenmodern ilaçların kullanımıyla beraber, geçtiğimiz yüzyılda böbrek hastalıklarıda dahil olmak üzere, ölümcül olan birçok hastalık artık tedavi edilebilirkonuma gelmiştir. Böbrek nakli, elde edilen başarılar ile beraber, hem böbrek hastalıkları için bir tedaviseçeneği haline gelmiş ve böbrek nakil oranları artış göstermiş, hem debeklenen yaşam süresi uzamıştır. Böbrek nakli yapılan hastaların cerrahisonrası tedavi süreçlerinde immünsüpresif ilaçlar kullanılmaktadır. Yenigeliştirilmeye çalışılan tedavi seçenekleri ile hem böbrek naklinde elde edilenbaşarı oranı arttırılmaya çalışılmakta hem de immünsüpresif ilaçlarınkullanımının yol açtığı yan etkilerin giderilmesi amaçlanmaktadır. Hücreseltedaviler de böbrek naklinde kullanılması için üzerinde çalışılan tedaviseçeneklerinden bir tanesidir. Regülatör T hücreler, regülatör B hücreler, regülatörmakrofajlar, dendritik hücreler, mezenkimal kök hücreler, organ nakillerindekullanılması için araştırma ve deneme yapılan hücre kaynaklarındandır. Deneyhayvanlarında nakil modellerinde yapılan çalışmalarda, hücre tedavileri ilebaşarılı sonuçlar alındığı gösterilmiştir. Bu derlemede böbrek naklindekullanılan ve de kullanılmaya aday olan hücre tedavileri tartışılmıştır.

 Böbrek Nakli hücre tedavisi regülatör T hücre tedavisi dendritik hücre tedavisi mezenkimal kök hücre tedavisi Renal transplantation cell therapy regulatory T cell therapy dendritic cell therapy mesenchymal stem cell therapy Referans1 Alikhan MA, Huynh M, Kitching AR, Ooi JD. Regulatory T cells in renal disease. Clin Transl Immunol 2018;7:1004-9. Referans2 Lamb KE, Lodhi S, Meier-Kriesche H-U. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011;11:450-62. Referans3 Stallone G, Infante B, Grandaliano G. Management and prevention of post-transplant malignancies in kidney transplant recipients. Clin Kidney J 2015;8:637-44. Referans4 Wood KJ, Goto R. Mechanisms of rejection: current perspectives. Transplantation 2012;93:1–10. Referans5 Lechler RI, Lombardi G, Richard Batchelor J, Reinsmoen N, Bach FH. The molecular basis of alloreactivity. Immunol Today 1990;11:83-8. Referans6 Zhuang Q, Lakkis FG. Dendritic cells and innate immunity in kidney transplantation. Kidney Int 2015;87:712-18. Referans7 Matzinger P, Bevan MJ. Why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol 1977;29:1-5. Referans8 Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells D, Turka L. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 2001;166:973-81. Referans9 Liu Z, Fan H, Jiang S. CD4 + T-cell subsets in transplantation. Immunol Rev 2013;252:183-91. Referans10 Rosenberg AS, Mizuochi T, Sharrow SO, Singer A. Phenotype, specificity, and function of T cell subsets and T cell interactions involved in skin allograft rejection. J Exp Med 1987;165:1296-315. Referans11 Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: Implications for graft rejection and transplantation tolerance. Curr Opin Immunol 2004;16(5):550-7. Referans12 Lee CY, Lotfi-Emran S, Erdinc M, Murata K, Velidedeoglu E, Fox-Talbot K, et al. The involvement of fcr mechanisms in antibody-mediated rejection. Transplantation 2007;84:1324-34. Referans13 Williams MA, Bevan M. Effector and Memory CTL Differentiation. Annu Rev Immunol 2007;25:171-92. Referans14 Valujskikh A, Lakkis FG. In remembrance of things past: Memory T cells and transplant rejection. Immunol Rev 2003;196:65-74. Referans15 Noris M, Casiraghi F, Todeschini M, Cravedi P, Cugini D, Monteferrante G, et al. Regulatory T Cells and T Cell Depletion: Role of Immunosuppressive Drugs. J Am Soc Nephrol 2007;18:1007-18. Referans16 Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 2005;5:465-74 Referans17 Page AJ, Ford ML, Kirk AD. Memory T-cell-specific therapeutics in organ transplantation. Curr Opin Organ Transplant 2009;14:643-49. Referans18 Rudensky AY. Regulatory T Cells and Foxp3. Immunol Rev 2011;241:260-8. Referans19 Waldmann H, Hilbrands R, Howie D, Cobbold S: Harnessing FOXP3+ regulatory T cells for transplantation tolerance. J Clin Invest 2014;124:1439-45. Referans20 Marín E, Cuturi MC, Moreau A. Tolerogenic dendritic cells in solid organ transplantation: Where do we stand? Front Immunol 2018;9:274-6. Referans21 Chabannes D, Hill M, Merieau E, Rossignol J, Brion R, Soulillou JP, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 2007;110(10):3691-4. Referans22 Franquesa M, Hoogduijn MJ, Reinders ME, Eggenhofer E, Engela AU, Mensah FK, et al. Mesenchymal stem cells in solid organ transplantation (MiSOT) fourth meeting: Lessons learned from first clinical trials. Transplantation 2013;96(3):234-8. Referans23 Riquelme P, Tomiuk S, Kammler A, Fändrich F, Schlitt HJ, Geissler EK, et al. IFN-γ-induced iNOS expression in mouse regulatory macrophages prolongs allograft survival in fully immunocompetent recipients. Mol Ther 2013;21(2):409-22. Referans24 Hill M, Thebault P, Segovia M, Louvet C, Bériou G, Tilly G, et al. Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and Epstein-Barr virus-induced gene 3. Am J Transplant 2011;11:2036-45. Referans25 Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology 2016;64(2):632-43. Referans26 Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973;137(5):1142-62. Referans27 Steinman R, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. II. Functional properties in vitro. J Exp Med. 1974;139(2):380-97. Referans28 Steinman RM, Lustig DS, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. 3 Functional properties in vivo. J Exp Med 1974;139(6):1431-45. Referans29 Steinman RM, Adams JC, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. IV. Identification and distribution in mouse spleen. J Exp Med 1975;141(4):804-20. Referans30 Steinman RM, Kaplan G, Witmer MD, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro. J Exp Med 1979;149(1):1-16. Referans31 Mukherji B, Chakraborty NG, Yamasaki S, Okino T, Yamase H, Sporn JR, et al. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci 1995;92(17):8078-82. Referans32 Mellman I. Dendritic cells: master regulators of the immune response. Cancer Immunol Res 2013;1(3):145-49. Referans33 Bustos-Morán E, Blas-Rus N, Martín-Cófreces NB, Sánchez-Madrid F. Orchestrating Lymphocyte Polarity in Cognate Immune Cell–Cell Interactions Int Rev Cell Mol Biol 2016;327:195-261. Referans34 Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol 2012;12(8):557-69. Referans35 Tisch R. Immunogenic versus tolerogenic dendritic cells: A matter of maturation. Int Rev Immunol 2010;29(2):111-8. Referans36 Hubo M, Trinschek B, Kryczanowsky F, Tuettenberg A, Steinbrink K, Jonuleit H. Costimulatory molecules on immunogenic versus tolerogenic human dendritic cells. Front Immunol 2013;4:82-7. Referans37 Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 2001;194:769-79. Referans38 Idoyaga J, Fiorese C, Zbytnuik L, Lubkin A, Miller J, Malissen B, et al. Specialized role of migratory dendritic cells in peripheral tolerance induction. J Clin Invest 2013;123(2):844-54. Referans39 Svajger U, Rozman P. Tolerogenic dendritic cells: molecular and cellular mechanisms in transplantation. J Leukoc Biol 2014;85(1):53-69. Referans40 Beriou G, Moreau A, Cuturi MC. Tolerogenic dendritic cells: Applications for solid organ transplantation. Curr Opin Organ Transplant 2012;17(1):42-7. Referans41 Yabu JM, Anderson MW, Kim D, Bradbury BD, Lou CD, Petersen J, et al. Sensitization from transfusion in patients awaiting primary kidney transplant. Nephrol Dial Transplant 2013;28(11):2908-18. Referans42 Alexander T, Sattler A, Templin L, Kohler S, Groß C, Meisel A, et al. Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis 2013;72(9):1549-58. Referans43 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057-61. Referans44 Raker VK, Domogalla MP, Steinbrink K. Tolerogenic dendritic cells for regulatory T cell induction in man. Front Immunol 201;6:569-72. Referans45 Allan SE, Broady R, Gregori S, Himmel ME, Locke N, Roncarolo MG, et al. CD4+ T-regulatory cells: Toward therapy for human diseases. Immunol Rev 2008;223:391-421. Referans46 Lam AJ, Hoeppli RE, Levings MK. Harnessing Advances in T Regulatory Cell Biology for Cellular Therapy in Transplantation. Transplantation 2017;101(10):2277-87. Referans47 Juvet SC, Whatcott AG, Bushell AR, Wood KJ. Harnessing regulatory t cells for clinical use in transplantation: The end of the beginning. Am J Transplant 2014;14(4):750-63. Referans48 Hoeppli RE, Macdonald KG, Levings MK, Cook L. How antigen specificity directs regulatory T-cell function: Self, foreign and engineered specificity. HLA 2016;88(1-2):3-13. Referans49 Duggleby R, Danby RD, Madrigal JA, Saudemont A. Clinical grade regulatory CD4+T cells (Tregs): Moving toward cellular-based immunomodulatory therapies. Front Immunol 2018;9:252-56. Referans50 Sicard A, Boardman DA, Levings MK. Taking regulatory T-cell therapy one step further. Curr Opin Organ Transplant 2018;23:509-15. Referans51 Dons EM, Raimondi G, Cooper DKC, Thomson AW. Non-Human Primate Regulatory T Cells: Current Biology and Implications for Transplantation. Transplantation 2010; 90(8):811-16. Referans52 Pilar F, Lourdes V, Dolores C, Pedro G-C, Lucia L, Jesus SM. Chronic graft-versus-host disease of the kidney in patients with allogenic hematopoietic stem cell transplant. Eur J Haematol 2013; 91(2):129-34. Referans53 Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol 2009; 133(1):22-6. Referans54 Tang Q, Lee K. Regulatory T-cell therapy for transplantation: How many cells do we need? Curr Opin Organ Transplant 2012;17(4):349-54. Referans55 Bocian K, Kiernozek E, Domagała-Kulawik J, Korczak-Kowalska G, Stelmaszczyk-Emmel A, Drela N. Expanding Diversity and Common Goal of Regulatory T and B Cells. I: Origin, Phenotype, Mechanisms. Archivum Immunologiae et Therapiae Experimentalis 2017;65(6):501-20. Referans56 Natarajan P, Singh A, McNamara JT, Secor ER, Guernsey LA, Thrall RS. Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF-β, and co-localize with CD4+Foxp3+T cells. Mucosal Immunol 2012; 5(6):691-701. Referans57 Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3(10):944-50. Referans58 Durand J CE. B cells with regulatory properties in transplantation tolerance. World J Transplant 2015;21:425-36. Referans59 Mauri C, Bosma A. Immune Regulatory Function of B Cells. Annu Rev Immunol 2012; 30:221-41. Referans60 Parker DC, Greiner DL, Phillips NE, Appel MC, Steele AW, Durie FH. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci 1995; 92(21):9560-64. Referans61 Niimi M, Pearson TC, Larsen CP, Alexander DZ, Hollenbaugh D, Aruffo A. The role of the CD40 pathway in alloantigen-induced hyporesponsiveness in vivo. J Immunol 1998; 161(10):5331-37. Referans62 Shabir S, Girdlestone J, Briggs D, Kaul B, Smith H, Daga S. Transitional B lymphocytes are associated with protection from kidney allograft rejection: A prospective study. Am J Transplant 2015; 15(5):1384-91. Referans63 Sun Q, Huang Z, Han F, Zhao M, Cao R, Zhao D. Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: Pilot results of a multicenter randomized controlled trial. J Transl Med 2018; 16(1):52-6. Referans64 English K, French A, Wood KJ. Mesenchymal stromal cells: Facilitators of successful transplantation? Cell Stem Cell 2010;7(4):431-42. Referans65 English K, Mahon BP. Allogeneic mesenchymal stem cells: Agents of immune modulation. Journal of Cellular Biochemistry 2011;112(8):1963-68. Referans66 Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4):315-7. Referans67 Bianco P. “Mesenchymal” Stem Cells. Annu Rev Cell Dev Biol 2014; 30:677-704. Referans68 Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L. Immunological characterization of multipotent mesenchymal stromal cells-The international society for cellular therapy (ISCT) working proposal. Cytotherapy 2013; 15(9):1054-61. Referans69 Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI. Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide. Cell Stem Cell 2008; 2(2):141-50. Referans70 Ren G, Su J, Zhang L, Zhao X, Ling W, L’Huillie A. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 2009; 27(8):1954-62. Referans71 Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001;2(10):907-16. Referans72 Mellor AL, Munn DH. IDO expression by dendritic cells: Tolerance and tryptophan catabolism. Nat Rev Immunol 2004; 4(10):762-74. Referans73 Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Differ 2014;21(2):216-25. Referans74 Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307(11):1169-77. Referans75 Reinders MEJ, Fijter JW De, Roelofs H, Bajema IM, Vries DK De, Schaapherder AF. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med 2013; 2(2):107-11. Referans76 Crop M, Baan C, Weimar W, Hoogduijn M. Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation. Transpl Int 2009; 22(4):365-76. Referans77 Peng Y, Ke M, Xu L, Liu L, Chen X, Xia W. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: A clinical pilot study. Transplantation 2013; 95(1):161-8. Referans78 Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Kao WW-Y. Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System. Ocul Surf 2016; 14(2):121-34. Referans79 Sivanathan KN, Gronthos S, Rojas-Canales D, Thierry B, Coates PT. Interferon-Gamma Modification of Mesenchymal Stem Cells: Implications of Autologous and Allogeneic Mesenchymal Stem Cell Therapy in Allotransplantation. Stem Cell Rev Reports 2014; 10(3):351-75. Referans80 Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA. Autologous Mesenchymal Stromal Cells and Kidney Transplantation: A Pilot Study of Safety and Clinical Feasibility. Clin J Am Soc Nephrol 2011;6(2):412-22. Referans81 Casiraghi F, Perico N, Cortinovis M, Remuzzi G. Mesenchymal stromal cells in renal transplantation: Opportunities and challenges. Nat Rev Nephrol 2016; 12(4):241-53. Referans82 Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L. A critical role of IFNγ in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res 2008; 18(8):846-.57 Referans83 Duijvestein M, Wildenberg ME, Welling MM, Hennink S, Molendijk I, Van Zuylen VL. Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 2011; 29(10):1549-58. Referans84 Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101(9):3722-29. Referans85 Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P. Veto-Like Activity of Mesenchymal Stem Cells: Functional Discrimination Between Cellular Responses to Alloantigens and Recall Antigens. J Immunol 2003; 171(7):3426-34. Referans86 Rafei M, Birman E, Forner K, Galipeau J. Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. Mol Ther 2009; 17(10):1799-803. Referans87 Schu S, Nosov M, O’Flynn L, Shaw G, Treacy O, et al. Immunogenicity of allogeneic mesenchymal stem cells. J Cell Mol Med 2012; 16(9):2094-103. Referans88 Badillo AT, Beggs KJ, Javazon EH, Tebbets JC, Flake AW. Murine Bone Marrow Stromal Progenitor Cells Elicit an In Vivo Cellular and Humoral Alloimmune Response. Biol Blood Marrow Transplant 2007; 13(4):412-22.