Journal List > J Korean Soc Transplant > v.28(3) > 1034424

Hee and Yang: Cell Therapy in Kidney Transplantation

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 im-munsuppressive 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.

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Table 1.
Impact of immunosuppressants on regulatory T cells
Drugs Impact on Tregs
Corticosteroid May support Tregs by reducing inflammation
Calcineurin inhibitors Detrimental to Tregs’ function and survival
Rapamycin Spare Tregs, thus increases proportion of Tregs
Mycophenolate mofetil Likely neutral
Antithymocyte globulin Deletes Tregs less efficiently, thus increase relative proportion of Tregs
Anti-CD25 Deletes Tregs
CTLA4-Ig Spares Tregs when used at subsaturating dose
Anti-LFA-1 Dramatically increases circulating Tregs proportion
Anti-CD40L Increases Tregs
Histone deacetylase inhibitors Improve homeostasis of Tregs
IL-2 or IL-2 complex Increases Tregs

Abbreviation: Tregs, regulatory T cells; CTLA4-Ig, Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein; LFA-1, lymphocyte function-associated antigen-1; IL-2, Interleukin-2.

Table 2.
Clinical application of mesenchymal stromal cells for living donor kidney transplantation
Author Patient number (MSCs vs. control) FU (month) Type of MSCs Time & route of MSC infusion Immunosuppression Efficacy Safety
Vanikar AV (65), Gujarat, India 606 vs. 310 (not randomized) 48 Donor, AT D3, IV DST/HST/TBI/RT X/ATG/CyP/IV IG/CS/CNI/ MMF (AZA) IS minimization (CNI withdrawal after 6 months), reduced AR None
Peng Y (66), Gu-angzhou, China 6 vs. 6 (randomized) 12 Donor, BM, 2∼5×106 D0 (IA), D30(IV) CyP/CS/CNI/MMF Reduced maintenance CNI dose None
Kim SJ (67), Seoul, Korea 7 12 Donor, BM, 1×106/kg D0, IO ATG/CS/CNI/MMF Increased Tregs and IL-10, in vitro donor-spe-cific hyporesponsiveness 3/6 AR
Perico N (68), Italy 2 12 Auto, BM, 2.0×106/kg D7, IV (D-1, IV) ATG/anti-CD25, CS/CsA/MMF Treg inhibition of memory T cells, in vitro donor-hyporesponsiveness Cr ↑ In 1∼2 week
Tan J (69), Fuzhou, China 102 vs. 51 (randomized) 12 Auto, BM, 1.2×106/kg D0 & D14, IV CS/CNI/MMF MSC1: standard CNI MSC2: low CNI Anti-CD25: standard Reduced maintenance CNI dose, early graft function (1 month eGFR), reduced AR (6 months), reduced infection None
Reinders ME (70), Netherlands 6 (Treatment for AR/IFTA) 5 Auto, BM, 1∼2×106/k g 6 months, IV ATG/CS/CNI/MMF, MSC: 2 doses with 1 week apart Reduced tubulitis, and IF/ TA, in vitro donor-hyporesponsiveness BKV, CMV

Abbreviations: aCD20, anti-CD20 antibody (Rituximab); aCD25, anti-CD25 antibody (Basiliximab); AE, adverse event; AT, adipose tissue; AZA, azathioprine; BM, bone marrow; CNI, calcineurin inhibitor(s); CyP, cyclophosphamide; DST, donor specific leukocyte transfusion; FU, follow-up; HSC, hematopoietic stem cells; IA, intraarterial; IF/TA, interstitial fibrosis/tubular atrophy; IO, intraosseous; IL, interleukin; IP, intraportal; IS, immunosuppression; IV, intravenous; LDKT, living donor kidney transplant; MMF, mycophenolate mofetil; MSC, mesenchymal stromal (stem) cell; RATG, rabbit anti-thymoglobulin.

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