Genes & CellsGenes & Cells2313-18292500-2562Human Stem Cells Institute12161310.23868/gc121613Research ArticleDecellularization as a prevention of immune response activation to allogeneic pulmonary valvesSergeevichevD. S-SergeevichevaV. V-SubbotovskayaA. I-VasilyevaM. B-DokuchayevaA. A-KaraskovA. M-KozlovV. A-E.N. Meshalkin Novosibirsk Research Institute of Circulation Pathology, NovosibirskResearch Institute of Clinical Immunology, SB of the RAMS, Novosibirsk1512201384556011012023Copyright © 2013, Eco-Vector2013The top priority of clinical immunology is the study of alloreactivity mechanisms and development of methods for prevention of transplanted organs rejection. The discharge of vascular and valvular prostheses from a non-functional cellular debris is effective way to reduce their immunogenicity in the post-transplant period and to extend their functional usefulness. Obviously, removal of the maximum amount of HLA-determinants in cell membranes using decellularization should lead to reduction of complication after heart valves allogeneic transplantation. However, the key mechanisms of the immune response during acellular biomatrix implantation are insufficiently studied. In this study we investigated the influence of preimplantation treatment of human cardiac valves on the in vitro expression of important lymphocytes regulators CD28 and CD152 (CTLA-4). We found a significant rise expression of CD8+28+ from 37,9% to 44,5%, CD8+152+ from 0,3% to 22,6%, CD4+28+ from 96,4% to 98,4% and CD4+152+ from 0,04% to 43,8%, p<0,05 on lymphocytes after cultivation with native valves fragments and valves after cryopreservation, that indicated T-cells activation in the presence of cellular antigens. In contrast, no difference was found in the quantitative expression of CD28 and CD152 on T-lymphocytes after culturing with decellularized valves in comparison with the control, that indicating the absence of T-cell response to allogeneic acellular tissue matrix of the heart valves. Thus, from the point of applied immunology was shown that transplantation of decellularized allogeneic valve is preferable in comparison with native and cryopreserved grafts. Also identified candidate molecules of the transplantation immunity represent a possible therapeutic interest.CD28CTLA-4 (CD152)transplantation immunitycardiac allograftCD28CTLA-4 (CD152)lymphocytesтрансплантационный иммунитетал-лографтлимфоциты[Cornwell K.G., Landsman A., James K.S. et al. Extracellular matrix biomaterial for soft tissue repair. Clin. Podiat. Med. Surg. 2009; 26(4): 507-23.][Troost E., Meyns B., Daenen W. et al. Homograft survival after tetralogy of Fallot repair: determinants of accelerated homograft degeneration. Euro. Heart J. 2007; 28(20): 2503-9.][Verghese S., Cherian K.M. HLA expression in aortic and pulmonary homografts: effects of cryopreservation. Indian Heart J. 2002; 54(4): 394-8.][Bloch O., Golde P., Dohmen P.M. et al. Immune response in patients receiving a bioprosthetic heart valve: lack of response with decellularized valves. Tissue Engineering, Part A 2011; 17(19-20): 2399-405.][Lehr E.J., Rayat G.R., Chiu B. et al. Decellularization reduces immunogenicity of sheep pulmonary artery vascular patches. J. Thor. Cardiovasc. Surg. 2011; 141: 1056-62.][Zhou J., Fritze O., Schleicher M. et al. Impact of heart valve decellularization on 3-D ultrastructure, immunogenicity and thrombogenicity. Biomaterials 2010; 31(9): 2549-54.][Guinan E.C., Gribben J.G., Boussiotis V.A. et al. Pivotal role of the B7: CD28 pathway in transplantation tolerance and tumor immunity. Blood 1994; 84(10): 3261-82.][Tsai M.K., Ho H.N., Chien H.F. et al. Multiple negative feedbacks on CD152 expression in allograft tolerance. Transplantation 2005; 79(2): 174-81.][Schmidt-Lucke C., Aicher A., Romagnani P. et al. Specific recruitment of CD4+CD25++ regulatory T cells into the allograft in heart transplant recipients. Amer. J. Physiol. Heart Circ. Physiol. 2007; 292(5): H2425-31.][Duan Z., Zhang Y., Pan F. et al. Association between CTLA4 gene polymorphisms and acute rejection of kidney transplantation: a meta-analysis. Nephrology 2012; 25(6): 996-1002.][Jashari R., Goffin Y., Vanderkelen A. et al. European homograft bank: twenty years of cardiovascular tissue banking and collaboration with transplant coordination in Europe. Transpl. Proc. 2010; 42: 183-9.][Васильева М.Б., Сергеевичев Д.С., Юношев А.С. и др. Морфофункциональная оценка ферментативного и детергентного способов децеллюляризации сердечных аллографтов. Патология кровообращения и кардиохирургия 2012; 2: 77-80.][Сергеевичев Д.С., Сергеевичева В.В., Субботовская А.И. и др. Токсическое влияние детергентов на мезенхимальные стро-мальные клетки человека при заселении графтов. Патология кровообращения и кардиохирургия 2013; 2: 67-71.][Alegre M., Fallarino F., Zhou P. et al. Transplantation and the CD28/CTLA4/B7 pathway. Transpl. Proc. 2001; 33(1-2): 209-11.][Studer S.M., George M.P., Zhu X. et al. CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients. Amer. J. Resp. Crit. Care Med. 2008; 178(7): 765-73.][Poirier N, Azimzadeh A.M, Zhang T. et al. Inducing CTLA-4 - dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Scien. Transl. Med. 2010; 2(17): 17ra10.][Dai S.X., Wu G., Zou Y. et al. Balance of CD8+ CD28+ / CD8+ CD28- T lymphocytes is vital for patients with ulcerative colitis. Digest. Dis. Sci. J. 2013; 58(1): 88-96.][Kucharska A.M., Gorska E., Wasik M. et al. Altered expression of T lymphocyte surface markers in children with chronic autoimmune thyroiditis. Nat. J. Physiol. Pharm. Pharmacol. 2008; 59, Suppl. 6: 375-82.][Greene J.L., Leytze G.M., Emswiler J. et al. Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions. J. Biol. Chem. 1996; 271(43): 26762-71.][Van der Merwe P.A., Bodian D.L., Daenke S. et al. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J. Exper. Med. 1997; 185: 393-403.]