Cell Therapy in Kidney Transplantation

Jung Jeon Hee; Jaeseok Yang

doi:10.4285/jkstn.2014.28.3.121

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Hee and Yang: Cell Therapy in Kidney Transplantation

Review Article

J Korean Soc Transplant 2014;28(3):121-134.

Published online: 10 September 2014

DOI: https://doi.org/10.4285/jkstn.2014.28.3.121

Cell Therapy in Kidney Transplantation

Jung Jeon Hee, M.D.¹, Jaeseok Yang, M.D.^1,²

¹Transplantation Center, Seoul National University Hospital Korea

²Transplantation Research Institute, Seoul National University College of Medicine², Seoul, Korea

Transplantation Center, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: 82-2-2072-4128, Fax: 82-2-2072-4129 E-mail: jcyjs@dreamwiz.com A portion of this work was presented at 15th symposium of Kidney Society of Transplant Nephrologists on June 28, 2014.

Received 20 August 2014 Revised 29 August 2014 Accepted 29 August 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Keywords: Cell therapy, Kidney transplantation

References

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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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