Journal of Evidence-Based Medicine ISSN 1756-5391
REVIEW ARTICLE
Adoptive transfusion of tolerogenic dendritic cells prolongs the survival of liver allograft: a systematic review Meng Juan Xia1 , Juan Shan1 , You Ping Li1,2 , Yan Ni Zhou1 , Ying Jia Guo1 , Gui Xiang Sun1 , Wen Qiao Wu1 and Li Feng1 1
Key Laboratory of Transplant Engineering and Immunology of National Health and Family Planning Commission of the People’s Republic of China, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu, China 2 Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, Chengdu, China
Keywords Adoptive transfusion; liver allograft; systematic review; tolerogenic dendritic cell (Tol-DC). Correspondence Professor Youping Li, Key Laboratory of Transplant Engineering and Immunology of National Health and Family Planning Commission of the People’s Republic of China, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Tel: 86-28-85164032; Fax: 86-28-85164034; Email: [email protected] Received 16 January 2014; accepted for publication 25 February 2014. doi: 10.1111/jebm.12094
Abstract Objectives: To systematically review the effects of tolerogenic dendritic cells (Tol-DCs) induced by different methods on liver transplantation and their possible mechanisms of action. Methods: PubMed and EMbase were searched for relevant articles through 31 December 2013. The effects of Tol-DCs on liver allograft survival were semiquantitatively evaluated, and the possible mechanisms by which Tol-DCs prolong graft survival were analyzed. Results: Seven articles were included, and classified according to methods of induction, sources, and methods of infusing Tol-DCs. Tol-DCs induced from immature DCs (imDCs), with cytokines, and by gene modification induced liver transplant tolerance for 33.1 ± 32.5 days (2.7-fold vs. control), 26.17 ± 16.20 days (1.8-fold vs. control), and 11.7 ± 1.6 days (2.3-fold vs. control), respectively. DCs derived from recipient bone marrow, donor bone marrow, and donor spleen induced liver transplant tolerance for 51.0 ± 0.0 days (5.9-fold vs. control), 21.4 ± 26.8 days (2.4-fold vs. control), and 15.0 ± 0.0 days (2.3-fold vs. control), respectively. The primary mechanisms by which Tol-DCs induce liver transplant tolerance were the induction of T-cell hyporeactivity and Th2 differentiation. Conclusions: Tol-DCs induced by three different methods could extend liver allograft survival, with imDCs showing optimal results. The optimal infusion method was intravenous injection of 1–2 × 106 Tol-DC, similar to findings in renal transplantation. Tol-DCs prolonged liver transplant tolerance more than renal transplant tolerance.
Introduction Liver transplantation is the most effective means of curing end-stage liver disease, such as primary liver cancer, congenital biliary atresia, and advanced hepatocirrhosis. Since the first report of liver transplantation, in 1963, in which two of three people died from acute rejection (1, 2), liver transplant techniques and immunosuppressants have improved, resulting in a dramatic reduction in the incidence of acute rejection. Long-term use of immunosuppressants, which inhibit recipient immune responses, can effectively inhibit acute rejection
but increase the risk of developing cardiovascular disease, infection, and cancer, under other conditions (3, 4). Chronic rejection can also affect long-term liver allograft survival and functional capacity (4–6). Effective and safe therapeutic options that reduce dependence on lifelong immunosuppressants are urgently needed. Dendritic cells (DCs), which derive primarily from the bone marrow, as well as from the liver and the spleen, and are characterized by heterogeneity of phenotype and maturity, can regulate immune responses by a dual mechanism (7). As the most effective professional antigen-presenting
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
135
Adoptive transfusion
M. J. Xia et al.
cells, DCs not only can activate T cells, but also can induce immune tolerance by inducing regulatory T cells (3, 8). Generally, mature DCs (mDCs) mediate immune responses, while tolerogenic DCs (Tol-DCs) with an immature DC (imDC) phenotype can induce specific T-cell hyporesponsiveness and immune tolerance (9). However, inflammatory mediators induced by organ transplantation can cause imDCs to mature gradually and lose the ability to induce tolerance. In the sixth of this series of systematic reviews, we systematically searched for and classified studies on the ability of Tol-DCs to induce immune tolerance to liver allografts and comprehensively reviewed the main mechanisms of action of Tol-DCs induced by different induction methods. These findings may guide the development of a new way of studying allograft tolerance.
Methods Inclusion and exclusion criteria Studies were included if they were published in Chinese or English; if they addressed liver transplant into rodent recipients; and if the research aimed at assessing the effects of adoptive infusion of Tol-DCs on liver graft survival. Review articles, abstracts, and in vitro experiments were excluded. If articles with similar data were published by the same group, only the article containing the most complete information was included.
Literature search PubMed and EMbase were searched for relevant articles through 31 December 2013, with ‘dendritic cells’, ‘liver transplantation’, and ‘liver allograft’ used as MeSH headings or text words.
Data extraction Based on our purpose and Participants, Intervention, Comparition, Outcome indicator, study design (PICOS) principle, the information of the included articles were extracted, including the strains of mice; the sources and intervention targets of Tol-DCs; the timing, method, frequency, and dose of Tol-DC administration; liver allograft survival time; and possible mechanisms of action. Important unreported data were obtained by consulting with corresponding authors, if possible.
Quality assessment Studies were screened according to the inclusion and exclusion criteria. Differences were discussed with Yanni Zhou
136
Table 1 Quality assessment Study ImDC Wang 2012 [3] Xie 2012 [4] Li 2011 [14] Xu 2004 [16] Total Gene modification Xie 2012 [4] Liu 2006 [15] Xu 2004 [16] Total Cytokine induction Sun 2012 [1] Deng 2008 [13] Total
1(2)
2(2)
3(2)
4(1)
Score
Grade
8
− − 6
− − − 6
4
7 6 4 4 5.3 ± 1.5
A A B B B
6
− − 2
− − − 3
3
6 4 4 4.7 ± 1.2
A B B B
4
− 2
− 3
2
4 7 5.5 ± 2.1
B A B
Studies using more than one method of inducing Tol-DCs were assigned to multiple groups. = conformity; – = not reported; – = information incomplete to meet the criteria (1 score). (1) = peer reviewed publication; (2) = random allocation to treatment or control; (3) = animal species (inbred, age-matched, MHC mismatch); (4) = sample size calculation, with sample sizes of the control and experimental groups clarified.
or resolved by other authors (Youping Li and Yinjia Guo). Article quality was based on four criteria (10, 11): 1. Peer-reviewed publication (2 points). 2. Random allocation to a treatment or control group (2 points). 3. Animal species (inbred strain, age-matched, statement of major histocompatibility complex (MHC) mismatch, 2 points). 4. Clarification of sample sizes of both control and experimental groups (1 point; Table 1). A mismatch in one criterion was scored as one-half a point. Papers selected were distributed into three levels, with levels A, B, and C indicating 6 points, Cytokin induction (1A) B (3A 4B) 198 29.80 ± 28.80 (2.6-fold) 39.1 ImDC (3A1B) > Cytokin induction (1A1B) > Gene modification (1A2B) A (6A) 138 30.29 ± 31.45 (4.2-fold) 37.74 A (1A) 20 0.20 ± 0.00 (1.0-fold) 21.6 A (5A) 30 22.00 ± 13.08 (2.1-fold) 33.49 B (2A3B) 166 24.50 ± 27.50 (2.7-fold) 39.24 B (1B) 20 15.00 ± 0.00 (2.3-fold) 27.00 A (2A) 103 43.40 ± 20.64 (6.7-fold) 51.08 B (1A3B) 74 36.50 ± 28.90 (3.0-fold) 55.10 A (4A) 122 21.38 ± 19.74 (3.9-fold) 28.75 A (6A) 81 20.88 ± 25.70 (3.6-fold) 29.05 A (1A) 10 82.50 ± 0.00 (5.7-fold) 100.00 A (1A) 14 69.10 ± 0.00 (9.2-fold) 77.50 A (5A) 86 19.65 ± 11.49 (2.07-fold) 37.96 B (1B) 10 51.00 ± 0.00 (5.9-fold) 61.40
A (16A)
Quality assessment (GRADE)
Differential
Summary of findings
M. J. Xia et al. Adoptive transfusion
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
143
Adoptive transfusion
M. J. Xia et al.
Tol-DC. Moreover, Tol-DCs infused intravenously into rats undergoing liver transplantation was more effective at inducing long-term graft survival than Tol-DCs infused into mice undergoing kidney transplantation. Portal vein infusion was found to be superior to intravenous infusion in mice undergoing kidney transplantation. In contrast, intravenous infusion was superior to portal vein infusion in rats undergoing both liver and kidney transplantation. A single dose of 1–2 × 106 Tol-DCs showed optimal results in both liver and kidney transplantation in rats. Kidney and liver allografts survived longer following the infusion of bone marrow-derived recipient than donor DCs, suggesting that donor DCs can lose their functions more easily and induce rejection responses than recipient DCs. Interestingly, pretreatment with semi-allogeneic (donor × recipient) F1 Tol-DCs or a mixture of donor and recipient DCs prolonged kidney allograft survival. To date, however, these types of Tol-DCs have not been tested in the using liver transplantation model.
Methods of DC culturing affect induction of tolerance DCs are usually obtained by culturing their progenitors with GM-CSF and IL-4, promoting cell differentiation and proliferation. DC phenotypes have been found to depend on GM-CSF concentrations. For example, GM-CSFlo alone mainly generated stable imDCs, whereas GM-CSFlo plus IL4 tended to generate mDCs, thus improving the purity and yield of DCs (29). The DCs generated by GM-CSFlo plus IL4 could still induce Th2 differentiation and prolong allograft survival (P < 0.05), but could not induce donor-specific tolerance (14). These DCs enhanced the production of IL-12p70 and IL-4, inducing humoral immune responses mediated by B cells (30). In contrast, GM-CSFhi induced a mixture of immature and mature DCs, with little effect on immunological tolerance (29). Preoperative infusion of GM-CSFhi DCs plus rapamycin was found to induce the conversion of a Th1 (IL-2 and IFN-γ ) to a Th2 (IL-4 and IL-10) response and significantly prolong allograft survival (3, 4, 16). Rapamycin has been shown to enhance the effects of Tol-DCs, increasing the proliferation of CD4+ CD25+ Foxp3+ Tregs (3, 31, 32).
metabolism, was found to play a role in immune regulation, with IDO activity correlated with the severity of acute rejection. The high expression of IDO in IFN-γ -modified DCs (IFN-γ -DC) led to Th2 differentiation, IL-2 upregulation, and lymphocytes apoptosis. Moreover, pre-injection of IFN-γ -DCs into transplant recipients prolonged graft survival time (1). Rats infused with imDCs performed better than those with cytokine-induced DCs, suggesting that a single cytokine affects only part of the signaling pathway. Thus, it may be easy to prolong allograft survival, but difficult to induce donor-specific tolerance, defined as recipient survival of >100 days. Moreover, GMlo -DCs were superior to GMhi DCs at inducing tolerance. Nuclear factor-κB (NF-κB) is a vital transcription factor that regulates the maturation of DCs and upregulates the MHC class II molecules CD80/86 and CD40. NF-κB decoy oligodeoxynucleotide-modified GMhi -DCs (NF-κB decoy ODNs GMhi -DCs) significantly enhanced tolerance and induced the regeneration of partial liver allografts by inhibiting the activity of NF-κB. These changes, in turn, reduced hepatocyte apoptosis, the activity of liver allograft-resident NK cells and IFN-γ production (16, 33). Gene-modified donor-derived DCs with downregulated RelB (a member of the NF-κB family) or upregulated TGF-β 1 was found to prolong allograft survival (4, 15, 34). In contrast, DCs modified by current target genes are insufficient to induce tolerance, suggesting that multiple induction methods may improve the ability to induce immune tolerance in Tol-DCs.
Limitation The reliability of our findings was subject to the research methods and quality of the primary studies. Our analysis was semiquantitative and descriptive, since a meta-analysis could not be performed because of incomplete data and low homogeneity. The study design was not as rigorous as studies that used inbred mice, and the mechanisms of action of DCs in liver transplantation remain unclear. In addition, there are no uniform standards to assess the quality of basic research, so the criteria we used remain to be tested.
Conclusion Method of inducing Tol-DCs affects allograft survival Cytokines can inhibit the maturation of Tol-DC and induce donor-specific T-cell hyporesponsiveness in vivo. The transfusion of GMhi -DCs modified by IL-10 (IL10-DCs) suppressed rejection and pathological changes (such as hemangiectasis and hyperemia) and performed better than GMhi DCs in prolonging allograft survival (13, 17). Indoleamine 2,3-dioxy-genase (IDO), an enzyme involved in tryptophan
144
Three types of Tol-DCs could extend liver allograft survival, with the optimal effect observed in the imDC group. Allograft survival time was prolonged 33.1 ± 32.5 days (2.7-fold higher than control). followed by cytokine induced (1.8-fold) and gene modified (2.3-fold) DCs. DCs derived from recipient bone marrow (51.0 ± 0.0 days, 5.9-fold) was superior to DCs derived from donor bone marrow (2.4-fold) and the spleen-derived donor DCs (2.3-fold). The optimal infusion method was intravenous injection of 1–2 × 106 Tol-DC, in
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
M. J. Xia et al.
Adoptive transfusion
agreement with findings for renal transplant. Tol-DCs was superior at inducing liver than renal transplant tolerance. 12.
Acknowledgements This work was financially supported by National Basic Research Program of China No. 2009CB522401, by the Natural Science Foundation of China (NSFC) no. 81270552 and 81273255, and by 2013 program of Key Laboratory of National Health and Family Planning Commission. None of the authors of this review has any conflict of interest. We thank Lei Luo and Chengwen Li for assistance in gathering articles and providing advice. References 1. Sun X, Gong ZJ, Wang ZW, et al. IDO-competent-DCs induced by IFN-γ attenuate acute rejection in rat liver transplantation. Journal of Clinical Immunology 2012; 32(4): 837–47. 2. Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surgery, Gynecology & Obstetrics 1963; 117: 659–76. 3. Wang GY, Yang Y, Li H, et al. Rapamycin combined with donor immature dendritic cells promotes liver allograft survival in association with CD4 (+) CD25 (+) Foxp3 (+) regulatory T cell expansion. Hepatology Research 2012; 42(2): 192–202. 4. Xie J, Wang Y, Bao J, et al. Immune tolerance induced by RelB short-hairpin RNA interference dendritic cells in liver transplantation. Journal of Surgical Research 2013; 180(1): 169–75. 5. Xie JM, Dong RQ, Li T, Zhang HY, Yao KH, Wen H. Establishment and evaluation of an acute rejection model of orthotopic liver transplantation in inbred rats. Journal of Clinical Rehabilitative Tissue Engineering Research 2011; 15(5): 778–82. 6. Fujiki M, Esquivel CO, Martinez OM, Strober S, Uemoto S, Krams SM. Induced tolerance to rat liver allografts involves the apoptosis of intragraft T cells and the generation of CD4(+)CD25(+)FoxP3(+) T regulatory cells. Liver Transplantation 2010; 16(2): 147–54. 7. Van Kooten C, Lombardi G, Gelderman KA, et al. Dendritic cells as a tool to induce transplantation tolerance: obstacles and opportunities. Transplantation 2011; 91(1): 2–7. 8. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4 +CD25+ FoxP3 + T cells. Bone Marrow Transplant 2007; 39(9): 537–45. 9. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annual Review of Immunology 2003; 21: 685–711. 10. Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004; 35(5): 1203–8. 11. Jonas S, Ayigari V, Viera D, Waterman P. Neuroprotection against cerebral ischemia: a review of animal studies and
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
correlation with human trial results. Annals of the New York Academy of Sciences 1999; 890: 2–3. Zhang CT, Shan J, Feng L, et al. Effects of immunosuppressive drugs on CD4+CD25 +regulatory T cells: a systematic review of clinical and basic research. Chinese Journal of Evidence-Based Medicine 2010; 3(2):117–29. Deng SX, Li JL, Ma Y. In vivo migration and immunoprotection of interleukin-10-modified dendritic cells in rats after heterogenic simultaneous liver-kidney transplantation. Journal of Clinical Rehabilitative Tissue Engineering Research 2008; 12(40): 7947–50. Li L, Zhang SN, Ran JH, Liu J, Li Z, Li LB. Mechanism of immune hyporesponsiveness induced by recipient-derived immature dendritic cells in liver transplantation rat. Chinese Medical Sciences Journal 2011; 26(1): 28–35. Liu N, Duan TD, Zheng N. Effects of TGF-beta1, gene modified donor dendritic cells on immune repulsion. Journal of Sichuan University (Medical Science Edition) 2006; 37(5): 721–5. Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Prolongation of liver allograft survival by dendritic cells modified with NF-kappaB decoy oligodeoxynucleotides. World Journal of Gastroenterology 2004; 10(16): 2361–8. Xia MJ, Shan J, Li YP, et al. Adoptive transfusion of tolerance dendritic cells prolong the survival of renal allograft: a systematic review on 16 animal studies. Journal of Evidence Based Medicine 2013; 6(4): 250–64. Yamaguchi J, Kanematsu T, Shiku H, Nakayama E. Longterm survival of orthotopic Lewis liver grafts in Wistar Furth rats. Elimination or inactivation of effector CTL and altered antigenicity as possible reasons for tolerance. Transplantation 1994; 57(3): 412–8. De Haan A, Van den Berg AP, Hepkema BG, et al. Donor-specific hyporeactivity after liver transplantation: prominent decreases in donor-specific cytotoxic T lymphocyte precursor frequencies independent of changes in helper T lymphocyte precursor frequencies or suppressor cell activity. Transplantation 1998; 66(4): 516–22. Qian SG, Thai NL, Lu LN, Fung JJ, Thomso AW. Liver transplant tolerance: mechanistic insights from animal models, with particular reference to the mouse. Transplantation Reviews 1997; 11(3): 151–64. Li YP, Tang Y, Li YS, Li LL, Diao X, Wen J. Organ specificity of chronic graft dysfunction: an analysis based on data of OPTN. Chinese Journal of Evidence-Based Medicine 2008; 8(11): 972–9. Lu J, Luo L, Guo Y, Long D, Wei L, Shan J, et al. The effect of MICA antigens on transplant outcomes: A systematic review. Journal of Evidence Based Medicine 2011; 4(2): 106–21. Bumgardner GL, Orosz CG. Unusual patterns of aloimmunity evoked by allogeneic liver parebchymal cels. Immunology Reviews 2000; 174(1): 260–79. Jiang G, Yang HR, Wang L, et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 2008; 86(11): 1492–502.
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
145
Adoptive transfusion
M. J. Xia et al.
25. Qian SG. Hepatic stellate cells and myeloid-derived suppressor cells in liver transplant immune tolerance. Chinese Journal of Transplantation 2010; 4(4): 301–3. 26. Hsieh CC, Chou HS, Yang HR, et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 2013; 121(10): 1760–8. 27. Corzo CA, Condamine T, Lu L, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. Journal of Experimental Medicine 2010; 207(11): 2439–53. 28. Wang GY, Zhang Q, Yang Y, et al. Rapamycin combined with allogenic immature dendritic cells selectively expands CD4+CD25+Foxp3 +regulatory T cells in rats. Hepatobiliary & Pancreatic Diseases International 2012; 11(2): 203–8. 29. Lutz MB, Suri RM, Niimi M, et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. European Journal of Immunology 2000; 30(7): 1813–22. 30. Anderson AE, Sayers BL, Haniffa MA, et al. Differential regulation of naive and memory CD4+ T cells by alternatively
146
31.
32.
33.
34.
activated dendritic cells. Journal of Leukocyte Biology 2008; 84(1): 124–33. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells. Bone Marrow Transplant 2007; 39(9): 537–45. Singh AK, Horvath KA, Mohiuddin MM. Rapamycin promotes the enrichment of CD4(+)CD25(hi)FoxP3(+)T regulatory cells from naive CD4(+) T cells of baboon that suppress antiporcine xenogenic response in vitro. Transplantation Proceedings 2009; 41(1): 418–21. Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Augmented regeneration of partial liver allograft induced by nuclear factor-kB decoy oligodeoxynucleotides-modified dendritic cells. World Journal of Gastroenterology 2004; 10(4): 573–8. Bonham CA, Peng L, Liang X, et al. Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-kappa B oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig. Journal of Immunology 2002; 169(6): 3382–91.
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
REVIEW ARTICLE
Adoptive transfusion of tolerogenic dendritic cells prolongs the survival of liver allograft: a systematic review Meng Juan Xia1 , Juan Shan1 , You Ping Li1,2 , Yan Ni Zhou1 , Ying Jia Guo1 , Gui Xiang Sun1 , Wen Qiao Wu1 and Li Feng1 1
Key Laboratory of Transplant Engineering and Immunology of National Health and Family Planning Commission of the People’s Republic of China, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu, China 2 Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, Chengdu, China
Keywords Adoptive transfusion; liver allograft; systematic review; tolerogenic dendritic cell (Tol-DC). Correspondence Professor Youping Li, Key Laboratory of Transplant Engineering and Immunology of National Health and Family Planning Commission of the People’s Republic of China, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Tel: 86-28-85164032; Fax: 86-28-85164034; Email: [email protected] Received 16 January 2014; accepted for publication 25 February 2014. doi: 10.1111/jebm.12094
Abstract Objectives: To systematically review the effects of tolerogenic dendritic cells (Tol-DCs) induced by different methods on liver transplantation and their possible mechanisms of action. Methods: PubMed and EMbase were searched for relevant articles through 31 December 2013. The effects of Tol-DCs on liver allograft survival were semiquantitatively evaluated, and the possible mechanisms by which Tol-DCs prolong graft survival were analyzed. Results: Seven articles were included, and classified according to methods of induction, sources, and methods of infusing Tol-DCs. Tol-DCs induced from immature DCs (imDCs), with cytokines, and by gene modification induced liver transplant tolerance for 33.1 ± 32.5 days (2.7-fold vs. control), 26.17 ± 16.20 days (1.8-fold vs. control), and 11.7 ± 1.6 days (2.3-fold vs. control), respectively. DCs derived from recipient bone marrow, donor bone marrow, and donor spleen induced liver transplant tolerance for 51.0 ± 0.0 days (5.9-fold vs. control), 21.4 ± 26.8 days (2.4-fold vs. control), and 15.0 ± 0.0 days (2.3-fold vs. control), respectively. The primary mechanisms by which Tol-DCs induce liver transplant tolerance were the induction of T-cell hyporeactivity and Th2 differentiation. Conclusions: Tol-DCs induced by three different methods could extend liver allograft survival, with imDCs showing optimal results. The optimal infusion method was intravenous injection of 1–2 × 106 Tol-DC, similar to findings in renal transplantation. Tol-DCs prolonged liver transplant tolerance more than renal transplant tolerance.
Introduction Liver transplantation is the most effective means of curing end-stage liver disease, such as primary liver cancer, congenital biliary atresia, and advanced hepatocirrhosis. Since the first report of liver transplantation, in 1963, in which two of three people died from acute rejection (1, 2), liver transplant techniques and immunosuppressants have improved, resulting in a dramatic reduction in the incidence of acute rejection. Long-term use of immunosuppressants, which inhibit recipient immune responses, can effectively inhibit acute rejection
but increase the risk of developing cardiovascular disease, infection, and cancer, under other conditions (3, 4). Chronic rejection can also affect long-term liver allograft survival and functional capacity (4–6). Effective and safe therapeutic options that reduce dependence on lifelong immunosuppressants are urgently needed. Dendritic cells (DCs), which derive primarily from the bone marrow, as well as from the liver and the spleen, and are characterized by heterogeneity of phenotype and maturity, can regulate immune responses by a dual mechanism (7). As the most effective professional antigen-presenting
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
135
Adoptive transfusion
M. J. Xia et al.
cells, DCs not only can activate T cells, but also can induce immune tolerance by inducing regulatory T cells (3, 8). Generally, mature DCs (mDCs) mediate immune responses, while tolerogenic DCs (Tol-DCs) with an immature DC (imDC) phenotype can induce specific T-cell hyporesponsiveness and immune tolerance (9). However, inflammatory mediators induced by organ transplantation can cause imDCs to mature gradually and lose the ability to induce tolerance. In the sixth of this series of systematic reviews, we systematically searched for and classified studies on the ability of Tol-DCs to induce immune tolerance to liver allografts and comprehensively reviewed the main mechanisms of action of Tol-DCs induced by different induction methods. These findings may guide the development of a new way of studying allograft tolerance.
Methods Inclusion and exclusion criteria Studies were included if they were published in Chinese or English; if they addressed liver transplant into rodent recipients; and if the research aimed at assessing the effects of adoptive infusion of Tol-DCs on liver graft survival. Review articles, abstracts, and in vitro experiments were excluded. If articles with similar data were published by the same group, only the article containing the most complete information was included.
Literature search PubMed and EMbase were searched for relevant articles through 31 December 2013, with ‘dendritic cells’, ‘liver transplantation’, and ‘liver allograft’ used as MeSH headings or text words.
Data extraction Based on our purpose and Participants, Intervention, Comparition, Outcome indicator, study design (PICOS) principle, the information of the included articles were extracted, including the strains of mice; the sources and intervention targets of Tol-DCs; the timing, method, frequency, and dose of Tol-DC administration; liver allograft survival time; and possible mechanisms of action. Important unreported data were obtained by consulting with corresponding authors, if possible.
Quality assessment Studies were screened according to the inclusion and exclusion criteria. Differences were discussed with Yanni Zhou
136
Table 1 Quality assessment Study ImDC Wang 2012 [3] Xie 2012 [4] Li 2011 [14] Xu 2004 [16] Total Gene modification Xie 2012 [4] Liu 2006 [15] Xu 2004 [16] Total Cytokine induction Sun 2012 [1] Deng 2008 [13] Total
1(2)
2(2)
3(2)
4(1)
Score
Grade
8
− − 6
− − − 6
4
7 6 4 4 5.3 ± 1.5
A A B B B
6
− − 2
− − − 3
3
6 4 4 4.7 ± 1.2
A B B B
4
− 2
− 3
2
4 7 5.5 ± 2.1
B A B
Studies using more than one method of inducing Tol-DCs were assigned to multiple groups. = conformity; – = not reported; – = information incomplete to meet the criteria (1 score). (1) = peer reviewed publication; (2) = random allocation to treatment or control; (3) = animal species (inbred, age-matched, MHC mismatch); (4) = sample size calculation, with sample sizes of the control and experimental groups clarified.
or resolved by other authors (Youping Li and Yinjia Guo). Article quality was based on four criteria (10, 11): 1. Peer-reviewed publication (2 points). 2. Random allocation to a treatment or control group (2 points). 3. Animal species (inbred strain, age-matched, statement of major histocompatibility complex (MHC) mismatch, 2 points). 4. Clarification of sample sizes of both control and experimental groups (1 point; Table 1). A mismatch in one criterion was scored as one-half a point. Papers selected were distributed into three levels, with levels A, B, and C indicating 6 points, Cytokin induction (1A) B (3A 4B) 198 29.80 ± 28.80 (2.6-fold) 39.1 ImDC (3A1B) > Cytokin induction (1A1B) > Gene modification (1A2B) A (6A) 138 30.29 ± 31.45 (4.2-fold) 37.74 A (1A) 20 0.20 ± 0.00 (1.0-fold) 21.6 A (5A) 30 22.00 ± 13.08 (2.1-fold) 33.49 B (2A3B) 166 24.50 ± 27.50 (2.7-fold) 39.24 B (1B) 20 15.00 ± 0.00 (2.3-fold) 27.00 A (2A) 103 43.40 ± 20.64 (6.7-fold) 51.08 B (1A3B) 74 36.50 ± 28.90 (3.0-fold) 55.10 A (4A) 122 21.38 ± 19.74 (3.9-fold) 28.75 A (6A) 81 20.88 ± 25.70 (3.6-fold) 29.05 A (1A) 10 82.50 ± 0.00 (5.7-fold) 100.00 A (1A) 14 69.10 ± 0.00 (9.2-fold) 77.50 A (5A) 86 19.65 ± 11.49 (2.07-fold) 37.96 B (1B) 10 51.00 ± 0.00 (5.9-fold) 61.40
A (16A)
Quality assessment (GRADE)
Differential
Summary of findings
M. J. Xia et al. Adoptive transfusion
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
143
Adoptive transfusion
M. J. Xia et al.
Tol-DC. Moreover, Tol-DCs infused intravenously into rats undergoing liver transplantation was more effective at inducing long-term graft survival than Tol-DCs infused into mice undergoing kidney transplantation. Portal vein infusion was found to be superior to intravenous infusion in mice undergoing kidney transplantation. In contrast, intravenous infusion was superior to portal vein infusion in rats undergoing both liver and kidney transplantation. A single dose of 1–2 × 106 Tol-DCs showed optimal results in both liver and kidney transplantation in rats. Kidney and liver allografts survived longer following the infusion of bone marrow-derived recipient than donor DCs, suggesting that donor DCs can lose their functions more easily and induce rejection responses than recipient DCs. Interestingly, pretreatment with semi-allogeneic (donor × recipient) F1 Tol-DCs or a mixture of donor and recipient DCs prolonged kidney allograft survival. To date, however, these types of Tol-DCs have not been tested in the using liver transplantation model.
Methods of DC culturing affect induction of tolerance DCs are usually obtained by culturing their progenitors with GM-CSF and IL-4, promoting cell differentiation and proliferation. DC phenotypes have been found to depend on GM-CSF concentrations. For example, GM-CSFlo alone mainly generated stable imDCs, whereas GM-CSFlo plus IL4 tended to generate mDCs, thus improving the purity and yield of DCs (29). The DCs generated by GM-CSFlo plus IL4 could still induce Th2 differentiation and prolong allograft survival (P < 0.05), but could not induce donor-specific tolerance (14). These DCs enhanced the production of IL-12p70 and IL-4, inducing humoral immune responses mediated by B cells (30). In contrast, GM-CSFhi induced a mixture of immature and mature DCs, with little effect on immunological tolerance (29). Preoperative infusion of GM-CSFhi DCs plus rapamycin was found to induce the conversion of a Th1 (IL-2 and IFN-γ ) to a Th2 (IL-4 and IL-10) response and significantly prolong allograft survival (3, 4, 16). Rapamycin has been shown to enhance the effects of Tol-DCs, increasing the proliferation of CD4+ CD25+ Foxp3+ Tregs (3, 31, 32).
metabolism, was found to play a role in immune regulation, with IDO activity correlated with the severity of acute rejection. The high expression of IDO in IFN-γ -modified DCs (IFN-γ -DC) led to Th2 differentiation, IL-2 upregulation, and lymphocytes apoptosis. Moreover, pre-injection of IFN-γ -DCs into transplant recipients prolonged graft survival time (1). Rats infused with imDCs performed better than those with cytokine-induced DCs, suggesting that a single cytokine affects only part of the signaling pathway. Thus, it may be easy to prolong allograft survival, but difficult to induce donor-specific tolerance, defined as recipient survival of >100 days. Moreover, GMlo -DCs were superior to GMhi DCs at inducing tolerance. Nuclear factor-κB (NF-κB) is a vital transcription factor that regulates the maturation of DCs and upregulates the MHC class II molecules CD80/86 and CD40. NF-κB decoy oligodeoxynucleotide-modified GMhi -DCs (NF-κB decoy ODNs GMhi -DCs) significantly enhanced tolerance and induced the regeneration of partial liver allografts by inhibiting the activity of NF-κB. These changes, in turn, reduced hepatocyte apoptosis, the activity of liver allograft-resident NK cells and IFN-γ production (16, 33). Gene-modified donor-derived DCs with downregulated RelB (a member of the NF-κB family) or upregulated TGF-β 1 was found to prolong allograft survival (4, 15, 34). In contrast, DCs modified by current target genes are insufficient to induce tolerance, suggesting that multiple induction methods may improve the ability to induce immune tolerance in Tol-DCs.
Limitation The reliability of our findings was subject to the research methods and quality of the primary studies. Our analysis was semiquantitative and descriptive, since a meta-analysis could not be performed because of incomplete data and low homogeneity. The study design was not as rigorous as studies that used inbred mice, and the mechanisms of action of DCs in liver transplantation remain unclear. In addition, there are no uniform standards to assess the quality of basic research, so the criteria we used remain to be tested.
Conclusion Method of inducing Tol-DCs affects allograft survival Cytokines can inhibit the maturation of Tol-DC and induce donor-specific T-cell hyporesponsiveness in vivo. The transfusion of GMhi -DCs modified by IL-10 (IL10-DCs) suppressed rejection and pathological changes (such as hemangiectasis and hyperemia) and performed better than GMhi DCs in prolonging allograft survival (13, 17). Indoleamine 2,3-dioxy-genase (IDO), an enzyme involved in tryptophan
144
Three types of Tol-DCs could extend liver allograft survival, with the optimal effect observed in the imDC group. Allograft survival time was prolonged 33.1 ± 32.5 days (2.7-fold higher than control). followed by cytokine induced (1.8-fold) and gene modified (2.3-fold) DCs. DCs derived from recipient bone marrow (51.0 ± 0.0 days, 5.9-fold) was superior to DCs derived from donor bone marrow (2.4-fold) and the spleen-derived donor DCs (2.3-fold). The optimal infusion method was intravenous injection of 1–2 × 106 Tol-DC, in
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
M. J. Xia et al.
Adoptive transfusion
agreement with findings for renal transplant. Tol-DCs was superior at inducing liver than renal transplant tolerance. 12.
Acknowledgements This work was financially supported by National Basic Research Program of China No. 2009CB522401, by the Natural Science Foundation of China (NSFC) no. 81270552 and 81273255, and by 2013 program of Key Laboratory of National Health and Family Planning Commission. None of the authors of this review has any conflict of interest. We thank Lei Luo and Chengwen Li for assistance in gathering articles and providing advice. References 1. Sun X, Gong ZJ, Wang ZW, et al. IDO-competent-DCs induced by IFN-γ attenuate acute rejection in rat liver transplantation. Journal of Clinical Immunology 2012; 32(4): 837–47. 2. Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surgery, Gynecology & Obstetrics 1963; 117: 659–76. 3. Wang GY, Yang Y, Li H, et al. Rapamycin combined with donor immature dendritic cells promotes liver allograft survival in association with CD4 (+) CD25 (+) Foxp3 (+) regulatory T cell expansion. Hepatology Research 2012; 42(2): 192–202. 4. Xie J, Wang Y, Bao J, et al. Immune tolerance induced by RelB short-hairpin RNA interference dendritic cells in liver transplantation. Journal of Surgical Research 2013; 180(1): 169–75. 5. Xie JM, Dong RQ, Li T, Zhang HY, Yao KH, Wen H. Establishment and evaluation of an acute rejection model of orthotopic liver transplantation in inbred rats. Journal of Clinical Rehabilitative Tissue Engineering Research 2011; 15(5): 778–82. 6. Fujiki M, Esquivel CO, Martinez OM, Strober S, Uemoto S, Krams SM. Induced tolerance to rat liver allografts involves the apoptosis of intragraft T cells and the generation of CD4(+)CD25(+)FoxP3(+) T regulatory cells. Liver Transplantation 2010; 16(2): 147–54. 7. Van Kooten C, Lombardi G, Gelderman KA, et al. Dendritic cells as a tool to induce transplantation tolerance: obstacles and opportunities. Transplantation 2011; 91(1): 2–7. 8. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4 +CD25+ FoxP3 + T cells. Bone Marrow Transplant 2007; 39(9): 537–45. 9. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annual Review of Immunology 2003; 21: 685–711. 10. Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004; 35(5): 1203–8. 11. Jonas S, Ayigari V, Viera D, Waterman P. Neuroprotection against cerebral ischemia: a review of animal studies and
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
correlation with human trial results. Annals of the New York Academy of Sciences 1999; 890: 2–3. Zhang CT, Shan J, Feng L, et al. Effects of immunosuppressive drugs on CD4+CD25 +regulatory T cells: a systematic review of clinical and basic research. Chinese Journal of Evidence-Based Medicine 2010; 3(2):117–29. Deng SX, Li JL, Ma Y. In vivo migration and immunoprotection of interleukin-10-modified dendritic cells in rats after heterogenic simultaneous liver-kidney transplantation. Journal of Clinical Rehabilitative Tissue Engineering Research 2008; 12(40): 7947–50. Li L, Zhang SN, Ran JH, Liu J, Li Z, Li LB. Mechanism of immune hyporesponsiveness induced by recipient-derived immature dendritic cells in liver transplantation rat. Chinese Medical Sciences Journal 2011; 26(1): 28–35. Liu N, Duan TD, Zheng N. Effects of TGF-beta1, gene modified donor dendritic cells on immune repulsion. Journal of Sichuan University (Medical Science Edition) 2006; 37(5): 721–5. Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Prolongation of liver allograft survival by dendritic cells modified with NF-kappaB decoy oligodeoxynucleotides. World Journal of Gastroenterology 2004; 10(16): 2361–8. Xia MJ, Shan J, Li YP, et al. Adoptive transfusion of tolerance dendritic cells prolong the survival of renal allograft: a systematic review on 16 animal studies. Journal of Evidence Based Medicine 2013; 6(4): 250–64. Yamaguchi J, Kanematsu T, Shiku H, Nakayama E. Longterm survival of orthotopic Lewis liver grafts in Wistar Furth rats. Elimination or inactivation of effector CTL and altered antigenicity as possible reasons for tolerance. Transplantation 1994; 57(3): 412–8. De Haan A, Van den Berg AP, Hepkema BG, et al. Donor-specific hyporeactivity after liver transplantation: prominent decreases in donor-specific cytotoxic T lymphocyte precursor frequencies independent of changes in helper T lymphocyte precursor frequencies or suppressor cell activity. Transplantation 1998; 66(4): 516–22. Qian SG, Thai NL, Lu LN, Fung JJ, Thomso AW. Liver transplant tolerance: mechanistic insights from animal models, with particular reference to the mouse. Transplantation Reviews 1997; 11(3): 151–64. Li YP, Tang Y, Li YS, Li LL, Diao X, Wen J. Organ specificity of chronic graft dysfunction: an analysis based on data of OPTN. Chinese Journal of Evidence-Based Medicine 2008; 8(11): 972–9. Lu J, Luo L, Guo Y, Long D, Wei L, Shan J, et al. The effect of MICA antigens on transplant outcomes: A systematic review. Journal of Evidence Based Medicine 2011; 4(2): 106–21. Bumgardner GL, Orosz CG. Unusual patterns of aloimmunity evoked by allogeneic liver parebchymal cels. Immunology Reviews 2000; 174(1): 260–79. Jiang G, Yang HR, Wang L, et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 2008; 86(11): 1492–502.
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
145
Adoptive transfusion
M. J. Xia et al.
25. Qian SG. Hepatic stellate cells and myeloid-derived suppressor cells in liver transplant immune tolerance. Chinese Journal of Transplantation 2010; 4(4): 301–3. 26. Hsieh CC, Chou HS, Yang HR, et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 2013; 121(10): 1760–8. 27. Corzo CA, Condamine T, Lu L, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. Journal of Experimental Medicine 2010; 207(11): 2439–53. 28. Wang GY, Zhang Q, Yang Y, et al. Rapamycin combined with allogenic immature dendritic cells selectively expands CD4+CD25+Foxp3 +regulatory T cells in rats. Hepatobiliary & Pancreatic Diseases International 2012; 11(2): 203–8. 29. Lutz MB, Suri RM, Niimi M, et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. European Journal of Immunology 2000; 30(7): 1813–22. 30. Anderson AE, Sayers BL, Haniffa MA, et al. Differential regulation of naive and memory CD4+ T cells by alternatively
146
31.
32.
33.
34.
activated dendritic cells. Journal of Leukocyte Biology 2008; 84(1): 124–33. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells. Bone Marrow Transplant 2007; 39(9): 537–45. Singh AK, Horvath KA, Mohiuddin MM. Rapamycin promotes the enrichment of CD4(+)CD25(hi)FoxP3(+)T regulatory cells from naive CD4(+) T cells of baboon that suppress antiporcine xenogenic response in vitro. Transplantation Proceedings 2009; 41(1): 418–21. Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Augmented regeneration of partial liver allograft induced by nuclear factor-kB decoy oligodeoxynucleotides-modified dendritic cells. World Journal of Gastroenterology 2004; 10(4): 573–8. Bonham CA, Peng L, Liang X, et al. Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-kappa B oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig. Journal of Immunology 2002; 169(6): 3382–91.
C 2014 Chinese Cochrane Center, West China Hospital of Sichuan University and Wiley Publishing Asia Pty Ltd JEBM 7 (2014) 135–146
