J Korean Soc Transplant.  2014 Sep;28(3):121-134. 10.4285/jkstn.2014.28.3.121.

Cell Therapy in Kidney Transplantation

Affiliations
  • 1Transplantation Center, Seoul National University Hospital, Seoul, Korea. jcyjs@dreamwiz.com
  • 2Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Abstract

Current immunosuppressants have nonspecific immuosuppressive effects, and are not helpful for tolerance induction. Consequently, transplant patients cannot discontinue using them, and their nonspecific immunosuppressive effects result in many side effects, including infection and malignancy. However, most of cellular immunotherapy can have donor antigen-specific immunsuppressive effects. Therefore, cell therapy could be an alternative or adjunctive to nonspecific immunosuppressants. Polyclonal or antigen-specific Foxp3+ regulatory T cells have been actively tried for prevention of acute rejection, treatment of chronic rejection, or tolerance induction in clinical trials. Regulatory macrophages are also under clinical trials for kidney transplant patients. IL-10-secreting type 1 regulatory T cells and donor- or recipient-derived tolerogenic dendritic cells will also be used for immunoregulation in clinical trials of kidney transplantation. These cells have antigen-specific immunoregulatory effects. Mesenchymal stromal cells (MSCs) have good proliferative capacity and immunosuppressive actions independently of major histocompatibility complex; therefore, even third-party MSCs can be stored and used for many patients. Cell therapy using various immunoregulatory cells is now promising for not only reducing side effects of nonspecific immunosuppressants but also induction of immune tolerance, and is expected to contribute to better outcomes in transplant patients.

Keyword

Cell therapy; Kidney transplantation

MeSH Terms

Cell- and Tissue-Based Therapy*
Dendritic Cells
Humans
Immune Tolerance
Immunosuppressive Agents
Immunotherapy
Kidney
Kidney Transplantation*
Macrophages
Major Histocompatibility Complex
Mesenchymal Stromal Cells
T-Lymphocytes, Regulatory
Tissue Donors
Immunosuppressive Agents

Reference

References

1). The U.S. National Institutes of Health. ClinicalTrials.gov [Internet]. Bethesda, MD: U.S. National Library of Medicine;1993. [cited 2014 May 13]. Available from: www.clinicaltrials.gov/.
2). Geissler EK. The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells. Transplant Res. 2012; 1:11.
Article
3). Trzonkowski P, Bieniaszewska M, Juś ciń ska J, Dobyszuk A, Krzystyniak A, Marek N, et al. 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; 133:22–6.
4). Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011; 117:1061–70.
Article
5). Di Ianni M1. Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011; 117:3921–8.
6). Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Gra-bowska M, Techmanska I, Juscinska J, et al. Administration of CD4+CD25highCD127-regulatory T cells preserves be-ta-cell function in type 1 diabetes in children. Diabetes Care. 2012; 35:1817–20.
7). Meagher C, Tang Q, Fife BT, Bour-Jordan H, Wu J, Pardoux C, et al. Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice. J Immunol. 2008; 180:7793–803.
Article
8). Joffre O1. Santolaria T, Calise D, Al Saati T, Hudrisier D, Romagnoli P, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med. 2008; 14:88–92.
Article
9). Waldmann H. Tolerance can be infectious. Nat Immunol. 2008; 9:1001–3.
Article
10). Tang Q, Bluestone JA. Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb Perspect Med. 2013; 3:a015552.
Article
11). Muthukumar T, Dadhania D, Ding R, Snopkowski C, Naqvi R, Lee JB, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med. 2005; 353:2342–51.
12). Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007; 8:1353–62.
Article
13). Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008; 9:239–44.
Article
14). Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3 (+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol. 2011; 23:424–30.
15). Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+ CD25+ regulatory T cells promote experimental transplantation tolerance. Blood. 2007; 109:827–35.
16). Nishimura E, Sakihama T, Setoguchi R, Tanaka K, Sakaguchi S. Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells. Int Immunol. 2004; 16:1189–201.
Article
17). Fan Z, Spencer JA, Lu Y, Pitsillides CM, Singh G, Kim P, et al. In vivo tracking of ‘color-coded' effector, natural and induced regulatory T cells in the allograft response. Nat Med. 2010; 16:718–22.
Article
18). Tang Q, Lee K. Regulatory T-cell therapy for transplantation: how many cells do we need? Curr Opin Organ Transplant. 2012; 17:349–54.
19). Francis RS, Feng G, Tha-In T, Lyons IS, Wood KJ, Bushell A. Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. Eur J Immunol. 2011; 41:726–38.
Article
20). Verginis P, McLaughlin KA, Wucherpfennig KW, von Boehmer H, Apostolou I. Induction of antigen-specific regulatory T cells in wild-type mice: visualization and targets of suppression. Proc Natl Acad Sci U S A. 2008; 105:3479–84.
Article
21). Tsang JY, Tanriver Y, Jiang S, Leung E, Ratnasothy K, Lombardi G, et al. Indefinite mouse heart allograft survival in recipient treated with CD4 (+)CD25 (+) regulatory T cells with indirect allospecificity and short term immunosuppression. Transpl Immunol. 2009; 21:203–9.
22). Hoffmann P, Boeld TJ, Eder R, Albrecht J, Doser K, Piseshka B, et al. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant. 2006; 12:267–74.
Article
23). Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006; 203:1701–11.
24). Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4 (+)CD25high regulatory T cells. Blood. 2004; 104:895–903.
25). Putnam AL, Safinia N, Medvec A, Laszkowska M, Wray M, Mintz MA, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant. 2013; 13:3010–20.
Article
26). Battaglia M, Stabilini A, Draghici E, Gregori S, Mocchetti C, Bonifacio E, et al. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes. 2006; 55:40–9.
Article
27). Serafini G, Andreani M, Testi M, Battarra M, Bontadini A, Biral E, et al. Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia. Haematologica. 2009; 94:1415–26.
Article
28). Gagliani N, Jofra T, Stabilini A, Valle A, Atkinson M, Roncarolo MG, et al. Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant. Diabetes. 2010; 59:433–9.
Article
29). Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013; 19:739–46.
Article
30). Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, et al. Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol. 2011; 41:1652–62.
Article
31). Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a longterm antigen-specific aner-gic state in human CD4+ T cells. J Exp Med. 1996; 184:19–29.
Article
32). Schwartz RH. T cell anergy. Annu Rev Immunol. 2003; 21:305–34.
Article
33). Zeller JC, Panoskaltsis-Mortari A, Murphy WJ, Ruscetti FW, Narula S, Roncarolo MG, et al. Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta. J Immunol. 1999; 163:3684–91.
34). Bacchetta R, Lucarelli B, Sartirana C, Gregori S, Lupo Stanghellini MT, Miqueu P, et al. Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol. 2014; 5:16.
Article
35). Ezzelarab M, Thomson AW. Tolerogenic dendritic cells and their role in transplantation. Semin Immunol. 2011; 23:252–63.
Article
36). Beriou G, Moreau A, Cuturi MC. Tolerogenic dendritic cells: applications for solid organ transplantation. Curr Opin Organ Transplant. 2012; 17:42–7.
37). Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol. 2007; 7:610–21.
Article
38). Divito SJ, Wang Z, Shufesky WJ, Liu Q, Tkacheva OA, Montecalvo A, et al. Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation. Blood. 2010; 116:2694–705.
Article
39). Taner T, Hackstein H, Wang Z, Morelli AE, Thomson AW. Rapamycin-treated, alloantigen-pulsed host dendritic cells induce ag-specific T cell regulation and prolong graft survival. Am J Transplant. 2005; 5:228–36.
Article
40). Bé riou G, Pê che H, Guillonneau C, Merieau E, Cuturi MC. Donor-specific allograft tolerance by administration of recipient-derived immature dendritic cells and suboptimal immunosuppression. Transplantation. 2005; 79:969–72.
Article
41). Hill M, Thebault P, Segovia M, Louvet C, Bé riou 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.
Article
42). Moreau A, Hill M, Thé bault P, Deschamps JY, Chiffoleau E, Chauveau C, et al. Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman primates. FASEB J. 2009; 23:3070–7.
Article
43). Naranjo-Gó mez M, Raï ch-Regué D, Oñ ate C, Grau-Ló pez L, Ramo-Tello C, Pujol-Borrell R, et al. Comparative study of clinical grade human tolerogenic dendritic cells. J Transl Med. 2011; 9:89.
Article
44). Chitta S, Santambrogio L, Stern LJ. GMCSF in the absence of other cytokines sustains human dendritic cell precursors with T cell regulatory activity and capacity to differentiate into functional dendritic cells. Immunol Lett. 2008; 116:41–54.
Article
45). Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, et al. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-depe-ndent ILT4/HLA-G pathway. Blood. 2010; 116:935–44.
Article
46). Harry RA, Anderson AE, Isaacs JD, Hilkens CM. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann Rheum Dis. 2010; 69:2042–50.
Article
47). Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011; 34:2026–32.
Article
48). Hilkens CM, Isaacs JD, Thomson AW. Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol. 2010; 29:156–83.
Article
49). Hutchinson JA, Riquelme P, Geissler EK. Human regulatory macrophages as a cell-based medicinal product. Curr Opin Organ Transplant. 2012; 17:48–54.
Article
50). Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 2011; 187:2072–8.
Article
51). Murphy SP, Porrett PM, Turka LA. Innate immunity in transplant tolerance and rejection. Immunol Rev. 2011; 241:39–48.
Article
52). Casiraghi F, Remuzzi G, Perico N. Mesenchymal stromal cells to promote kidney transplantation tolerance. Curr Opin Organ Transplant. 2014; 19:47–53.
Article
53). Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002; 30:42–8.
Article
54). Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002; 99:3838–43.
Article
55). English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2013; 91:19–26.
Article
56). Chen HW, Chen HY, Wang LT, Wang FH, Fang LW, Lai HY, et al. Mesenchymal stem cells tune the development of monocyte-derived dendritic cells toward a mye-loid-derived suppressive phenotype through growth-regu-lated oncogene chemokines. J Immunol. 2013; 190:5065–77.
Article
57). Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013; 31:1980–91.
Article
58). Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a proinflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One. 2010; 5:e10088.
Article
59). Casiraghi F, Azzollini N, Todeschini M, Cavinato RA, Cassis P, Solini S, et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant. 2012; 12:2373–83.
Article
60). Hoogduijn MJ, Crop MJ, Korevaar SS, Peeters AM, Eijken M, Maat LP, et al. Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin. Transplantation. 2008; 86:1283–91.
Article
61). Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8:315–7.
Article
62). Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L. MSC Committee of the International Society for Cellular Therapy (ISCT). Immunological characterization of multipotent mesenchymal stromal cells–The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy. 2013; 15:1054–61.
Article
63). Vanikar AV, Trivedi HL, Feroze A, Kanodia KV, Dave SD, Shah PR. Effect of cotransplantation of mesenchymal stem cells and hematopoietic stem cells as compared to hematopoietic stem cell transplantation alone in renal transplantation to achieve donor hyporesponsiveness. Int Urol Nephrol. 2011; 43:225–32.
Article
64). Vanikar AV, Trivedi HL. Stem cell transplantation in living donor renal transplantation for minimization of immunosuppression. Transplantation. 2012; 94:845–50.
Article
65). Peng Y, Ke M, Xu L, Liu L, Chen X, Xia W, et al. Donor-de-rived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation. 2013; 95:161–8.
66). Lee H, Park JB, Lee S, Baek S, Kim H, Kim SJ. Intraosseous injection of donor mesenchymal stem cell (MSC) into the bone marrow in living donor kidney transplantation; a pilot study. J Transl Med. 2013; 11:96.
Article
67). Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011; 6:412–22.
Article
68). Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012; 307:1169–77.
69). Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, et al. Autologous bone marrowderived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med. 2013; 2:107–11.
Article
70). Pileggi A, Xu X, Tan J, Ricordi C. Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Curr Opin Organ Transplant. 2013; 18:672–81.
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