Splenectomy increases the survival time of heart allograft via developing immune tolerance

Journal of Cardiothoracic Surgery

Zhen Yao¹  Yanfang Chen⁴  Ruilian Ma⁴  Peng Liu¹  Wei Zhang³  Cheng Zhang⁴  Jinju Wang⁴  Shuzhen Chen⁴  Jinguo Zhu² 

[1] Department of Cardiology, The People’s Hospital of Sanya, Sanya, Hainan, 572000, China;Department of Cardiothoracic Surgery, The People’s Hospital of Sanya, Sanya, Hainan, 572000, China;Department of Pharmacology, The People’s Hospital of Sanya, Sanya, Hainan, 572000, China;Department of Pharmacology and Toxicology, Boonshoft School of Medicine of Wright State University, Dayton, OH, 45435, USA

关键词: Lymphocyte apoptosis;    CD₄⁺CD₂₅⁺ Treg;    Immune tolerance;    Heart transplantation;    Splenectomy;   

Others  :  824658
DOI  :  10.1186/1749-8090-8-129

 received in 2012-11-05, accepted in 2013-05-14,  发布年份 2013

【 摘 要 】

Background

The spleen is an active lymphoid organ. The effect of splenectomy on the immune response remains unclear. This study investigated whether splenectomy can induce immune tolerance and has a beneficial role in cardiac allograft.

Methods

Wistar rats were used for heart donors. The Sprague–Dawley (SD) rats designated as the recipients of heart transplantation (HT) were randomly assigned into four groups: sham, splenectomy, HT, splenectomy + HT. The survival of transplanted hearts was assessed by daily checking of abdominal palpation. At various time points after transplantation, the transplanted hearts were collected and histologically examined; the level of CD₄⁺CD₂₅⁺ T regulatory lymphocytes (Tregs) and rate of lymphocyte apoptosis (annexin-v⁺ PI⁺ cells) in the blood were analyzed by using flow cytometric method.

Results

1) Splenectomy significantly prolonged the mean survival time of heart allografts (7 ± 1.1 days and 27 ± 1.5 days for HT and splenectomy + HT, respectively; n = 12-14/group, HT vs. splenectomy + HT, p < 0.001); 2) Splenectomy delayed pathological changes (inflammatory cell infiltration, myocardial damage) of the transplanted hearts in splenectomy + HT rats; 3) The level of CD₄⁺CD₂₅⁺ Tregs in the blood of splenectomized rats was significantly increased within 7 days (2.4 ± 0.5%, 4.9 ± 1.3% and 5.3 ± 1.0% for sham, splenectomy and splenectomy + HT, respectively; n = 15/group, sham vs. splenectomy or splenectomy + HT, p < 0.05) after splenectomy surgery and gradually decreased to baseline level; 4) Splenectomy increased the rate of lymphocyte apoptosis (day 7: 0.3 ± 0.05%, 3.9 ± 0.9% and 4.1 ± 0.9% for sham, splenectomy and splenectomy + HT, respectively; n = 15/group, sham vs. splenectomy or splenectomy + HT, p < 0.05) in a pattern similar to the change of the CD₄⁺CD₂₅⁺ Tregs in the blood.

Conclusions

Splenectomy inhibits the development of pathology and prolongs the survival time of cardiac allograft. The responsible mechanism is associated with induction of immune tolerance via elevating CD₄⁺CD₂₅⁺ Tregs and increasing lymphocyte apoptosis.

【 授权许可】

   
2013 Zhu et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Patel JK, Kittleson M, Kobashigawa JA: Cardiac allograft rejection. Surgeon 2011, 9:160-167.
• [2]Sun Y, Chen X, Zhao J, Zou X, Li G, Li X, Shen B, Sun S: Combined use of rapamycin and leflunomide in prevention of acute cardiac allografts rejection in rats. Transpl Immunol 2012, 27:19-24.
• [3]Fu F, Li Y, Qian S, Lu L, Chambers F, Starzl TE, Fung JJ, Thomson AW: Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80dim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients. Transplantation 1996, 62:659-665.
• [4]Lindenfeld J, Miller GG, Shakar SF, Zolty R, Lowes BD, Wolfel EE, Mestroni L, Page RL, Kobashigawa J: Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. Circulation 2004, 110:3858-3865.
• [5]Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155:1151-1164.
• [6]Graca L, Thompson S, Lin CY, Adams E, Cobbold SP, Waldmann H: Both CD4(+)CD25(+) and CD4(+)CD25(−) regulatory cells mediate dominant transplantation tolerance. J Immunol 2002, 168:5558-5565.
• [7]Thomas F, Thomas J, Wolf JS, Schatzki P, Cohen C, Hume DM: Prevention of hyperacute kidney rejection by early splenectomy: etiologic and therapeutic implications. Surg Forum 1972, 23:261-263.
• [8]Carobbi A, Araneda D, Thomas F, Quarantillo P, Thomas J: Splenectomy is a potent immunosuppressive modality for cardiac xenografting. Transplant Proc 1993, 25:419-420.
• [9]Schwarz RE, Hiserodt JC: Effects of splenectomy on the development of tumor-specific immunity. J Surg Res 1990, 48:448-453.
• [10]Ono K, Lindsey ES: Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 1969, 57:225-229.
• [11]Schmid C, Binder J, Heemann U, Tilney NL: Successful heterotopic heart transplantation in rat. Microsurgery 1994, 15:279-281.
• [12]Fingerhuth H, Holschermann H, Grimm H, Tillmanns H, Haberbosch W, Braun-Dullaeus RC, Stadlbauer TH: 3-Deazaadenosine prevents leukocyte invasion by suppression of adhesion molecule expression during acute cardiac allograft rejection: involvement of apoptotic cell death. J Heart Lung Transplant 2004, 23:970-978.
• [13]Chen J, Chen S, Chen Y, Zhang C, Wang J, Zhang W, Liu G, Zhao B, Chen Y: Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage. Am J Physiol Endocrinol Metab 2011, 301:E62-E71.
• [14]Sakaguchi S: Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005, 6:345-352.
• [15]Levings MK, Sangregorio R, Roncarolo MG: Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001, 193:1295-1302.
• [16]Shevach EM: Regulatory T cells in autoimmmunity. Annu Rev Immunol 2000, 18:423-449.
• [17]Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM: Conversion of peripheral CD4+. J Exp Med 2003, 198:1875-1886.
• [18]Curotto de Lafaille MA, Lino AC, Kutchukhidze N, Lafaille JJ: CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J Immunol 2004, 173:7259-7268.
• [19]Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM: CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 2002, 196:237-246.
• [20]Dai Z, Li Q, Wang Y, Gao G, Diggs LS, Tellides G, Lakkis FG: CD4 + CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism. J Clin Invest 2004, 113:310-317.
• [21]Janssens W, Carlier V, Wu B, VanderElst L, Jacquemin MG, Saint-Remy JM: CD4 + CD25+ T cells lyse antigen-presenting B cells by Fas-Fas ligand interaction in an epitope-specific manner. J Immunol 2003, 171:4604-4612.
• [22]Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, Powell WS, Monneret G: Human CD4 + CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 2006, 177:6540-6547.
• [23]Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ: Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004, 21:589-601.
• [24]Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L: Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med 2000, 6:782-789.
• [25]Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Diaz M, Gallardo G: Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 2009, 31:245-258.
• [26]Radu CG, Shu CJ, Nair-Gill E, Shelly SM, Barrio JR, Satyamurthy N, Phelps ME, Witte ON: Molecular imaging of lymphoid organs and immune activation by positron emission tomography with a new [18F]-labeled 2′-deoxycytidine analog. Nat Med 2008, 14:783-788.
• [27]Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G: TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007, 131:1124-1136.
• [28]Sharland A, Yan Y, Wang C, Bowen DG, Sun J, Sheil AG, McCaughan GW, Bishop GA: Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance. Transplantation 1999, 68:1736-1745.