Cell therapy for immunosuppression after kidney transplantation
To give an overview over cell therapeutic approaches to immunosuppression in clinical kidney transplantation. A focus is on myeloid suppressor cell therapy by mitomycin C-induced cells (MICs).
Literature review with an emphasis on already existing therapies.
Several cell therapeutic approaches to immunosuppression and donor-specific unresponsiveness are now being tested in early phase I and phase II trials in clinical kidney transplantation. Cell products such as regulatory T cells or regulatory macrophages, or other myeloid suppressor cell therapies, may either consist of donor-specific, third-party, or autologous cell preparations. Major problems are the identification of the suppressive cell populations and their expansion to have sufficient amount of cells to achieve donor unresponsiveness (e.g., with regulatory T cells). We show a simple and safe way to establish donor unresponsiveness in living-donor kidney transplantation by MIC therapy. A phase I clinical trial is now under way to test the safety and efficacy of this cell therapeutic approach.
Cell therapeutic approaches to immunosuppression after kidney transplantation may revolutionize clinical transplantation in the future.
KeywordsTransplantation Immunosuppression Tolerance Regulatory T cells Myeloid suppressor cells Mitomycin C-induced cells
The TOL-1 study is funded by a grant from the German government (EXIST-Forschungstransfer: TolerogenixX, 03EFB BW56).
Conflicts of Interest
All procedures will perform in the planned TOL-1 study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent will obtain from all individual participants included in the study.
- 11.Schaier M, Seissler N, Becker LE, Schaefer SM, Schmitt E, Meuer S, Hug F, Sommerer C, Waldherr R, Zeier M et al (2013) The extent of HLA-DR expression on HLA-DR(+) Tregs allows the identification of patients with clinically relevant borderline rejection. Transpl Int 26(3):290–299PubMedCrossRefGoogle Scholar
- 15.Hutchinson JA, Geissler EK (2015) Now or never? The case for cell-based immunosuppression in kidney transplantation. Kidney IntGoogle Scholar
- 19.Kawai T, Sachs DH, Sprangers B, Spitzer TR, Saidman SL, Zorn E, Tolkoff-Rubin N, Preffer F, Crisalli K, Gao B et al (2014) Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am J Transplant 14(7):1599–1611PubMedCrossRefPubMedCentralGoogle Scholar
- 20.Tang Q, Bluestone JA (2013) Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb Perspect Med 3(11)Google Scholar
- 22.Gallon L, Traitanon O, Yu Y, Shi B, Leventhal JR, Miller J, Mas V, L X, Mathew JM (2015) Differential effects of calcineurin and mammalian target of rapamycin inhibitors on alloreactive Th1, Th17, and Regulatory T Cells. TransplantationGoogle Scholar
- 23.Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P et al (2015) Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant 15(3):695–704PubMedCrossRefGoogle Scholar
- 24.Leventhal JR, Elliott MJ, Yolcu ES, Bozulic LD, Tollerud DJ, Mathew JM, Konieczna I, Ison MG, Galvin J, Mehta J et al (2015) Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants. Transplantation 99(2):288–298PubMedCrossRefGoogle Scholar
- 29.van der Net JB, Bushell A, Wood KJ, Harden PN (2015) Regulatory T cells: first steps of clinical application in solid organ transplantation. Transpl IntGoogle Scholar
- 33.Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P et al (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117(3):1061–1070PubMedCrossRefPubMedCentralGoogle Scholar
- 35.Trzonkowski P, Bieniaszewska M, Juscinska J, Dobyszuk A, Krzystyniak A, Marek N, Mysliwska J, Hellmann A (2009) 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 133(1):22–26PubMedCrossRefGoogle Scholar
- 42.Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, Oberg HH, Pascher A, Lutzen U, Janssen U et al (2011) Cutting edge: immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 187(5):2072–2078PubMedCrossRefGoogle Scholar
- 47.Terness P, Oelert T, Ehser S, Chuang JJ, Lahdou I, Kleist C, Velten F, Hammerling GJ, Arnold B, Opelz G (2008) Mitomycin C-treated dendritic cells inactivate autoreactive T cells: toward the development of a tolerogenic vaccine in autoimmune diseases. Proc Natl Acad Sci U S A 105(47):18442–18447PubMedCrossRefPubMedCentralGoogle Scholar
- 49.Radu CA, Kiefer J, Horn D, Kleist C, Dittmar L, Sandra F, Rebel M, Ryssel H, Koellensperger E, Gebhard MM et al (2012) Mitomycin-C-treated peripheral blood mononuclear cells (PBMCs) prolong allograft survival in composite tissue allotransplantation. J Surg Res 176(2):e95–e101PubMedCrossRefGoogle Scholar