References

transplantologiya

Трансплантология

Transplantologiya. The Russian Journal of Transplantation

2074-05062542-0909

IPO Association of Transplantologists

transplantologiya-54

Research Article

ОБЗОРНЫЕ СТАТЬИ И ЛЕКЦИИ

REVIEW ARTICLES AND LECTURES

Индукционная иммуносупрессия при трансплантации почки: Тимоглобулин® (обзор литературы)

Induction immunosuppression in kidney transplantation: Thymoglobulin® (a literature review)

Пинчук

А. В.

Pinchuk

A. V.

avpin@rambler.ru

ГБУЗ «НИИ скорой помощи им. Н.В. Склифосовского ДЗ г. Москвы»РоссияSklifosovsky Research Institute for Emergency Medicine Public Healthcare Institution of Moscow Healthcare DepartmentRussian Federation

2014

02022016

Транспланталогия

3143

2016

Пинчук А.В.

Pinchuk A.V.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.jtransplantologiya.ru/jour/article/view/54

Кроличий антитимоцитарный иммуноглобулин – тимоглобулин – впервые был получен более 25 лет назад и в настоящее время является наиболее широко используемым антилимфоцитарным иммуноглобулином в трансплантации паренхиматозных органов. Тимоглобулин взаимодействует с широким диапазоном поверхностных антигенов Т-лимфоцитов, натуральных киллеров, В-лимфоцитов и плазматических клеток, а также с молекулами адгезии и рецепторами хемокинов, что приводит к длительной лимфопении. Рандомизированные исследования показали эффективность тимоглобулина в отношении профилактики острого отторжения трансплантата при пересадке почки. Экспериментальные и клинические исследования дают основание предполагать, что применение тимоглобулина может меньшить явления ишемически-реперфузионного повреждения (ИРП), снижая, таким образом, частоту случаев отсроченной функции трансплантата (ОФТ). Также данные исследования доказали преимущество тимоглобулина, связанное с минимизацией иммуносупрессии: отменой кортикостероидов и ингибиторов кальциневрина (CNI) и улучшением эффективности лечения в отношении сердечно-сосудистой системы и почек. Оптимальная кумулятивная доза тимоглобулина в режиме индукционной терапии составляет 6–7,5 мг/кг при условии мониторинга показателей лабораторных исследований крови.

На данный момент индукция тимоглобулином показана пациентам из группы высокого иммунологического риска (с повышенным риском ОФТ), а также в целях сохранения эффективности иммуносупрессии у реципиентов из группы стандартного риска, получающих терапию с использованием минимальных доз стероидов или ингибиторов CNI, либо же в случае их полной отмены.

Rabbit anti-thymocyte immunoglobulin, Thymoglobulin, was first obtained over 25 years ago and currently it is the most widely used antilymphocytic immunoglobulin in solid organ transplantation. Thymoglobulin interacts with a broad range of surface antigens of T-lymphocytes, natural killer cells, B-lymphocytes and plasma cells, as well as, withadhesion molecules and chemokine receptors, which results in a prolonged lymphopenia. Randomized studies have shown the effect of thymoglobulin on the prevention of acute graft rejection in kidney transplant. Experimental and clinicalstudies suggest that the use of thymoglobulin can reduce the impact of ischemia-reperfusion injury, thus reducing the incidence of delayed graft function (DGF). These studies have also shown the thymoglobulin advantage associated with minimizing the immunosuppression: the discontinuation of corticosteroids and calcineurin inhibitors (CNI) and with the improvement of treatment effect in relation to the cardiovascular system and kidneys. Optimal cumulative dose of Thymoglobulin in induction therapy scheme makes 6–7.5 mg/kg, provided monitoring via serial blood laboratory testsis performed.Currently, the induction with Thymoglobulin proved to be indicated for high immunological risk patients (increased DGF risk), and also for maintenance of immunosuppression effect in the standard risk group of kidney recipients receiving treatment with low doses of steroids and the calcineurin inhibitors (CNI), or in the cases of their complete withdrawal

тимоглобулиниммуносупрессиятрансплантация почки

Thymoglobulinimmunosuppressionrenal transplantation

References1

Gaber A.O., Monaco A.P., Russell J.A., et al. Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology. Drugs. 2010; 70 (6): 691–732.

Starzl T.E. Heterologous antilymphocyte globulin. N. Engl. J. Med. 1968; 279 (13): 700–703.

Starzl T.E., Porter K.A., Iwasaki Y., Marchioro T.L., Kashiwagi N. The use of heterologous antilymphocyte globulin in human renal homotransplantation. In: Wolstenholme GEW, O’Connor MJ, editors. Antilymphocytic Serum. London: J.& A. Churchill, Ltd; 1967. 4–34.

Brennan D.C., Daller J.A., Lake K.D., et al. Thymoglobin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N. Engl. J. Med. 2006; 355 (19): 1967–1977.

Bonnefoy-Bérard N., Vincent C., Revillard J.P. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation. 1991; 51 (3): 669–673.

Préville X., Flacher M., LeMauff B., et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation. 2001; 71 (3): 460–468.

Genestier L., Fournel S., Flacher M., et al. Induction of Fas (Apo-1, CD95)- ediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins. Blood. 1998; 91 (7): 2360–2368.

Michallet M.C., Saltel F., Preville X., et al. Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion. Blood. 2003;102 (10): 3719–3726.

Merion R.M., Howell T., Bromberg J.S. Partial T-cell activation and anergy induction by polyclonal antithymocyte globulin. Transplantation. 1998; 65 (11): 1481–1489.

Diethelm A.G., Aldrete J.S., Shaw J.F., et al. Clinical evaluation of equine ntithymocyte globulin in recipients of renal allograft: analysis of survival, renal function, rejection, histocompatibility, and complications. Ann. Surg. 1974; 180 (1):20–28.

Najarian J.S., Simmons R.L., Condie R.M., et al. Seven years’ experience with antilymphoblast globulin for renal transplantation from cadaver donors. Ann. Surg. 1976; 184 (3): 352–368.

Uslu A., Nart A. Treatment of first acute rejection episode: systematic review of level I evidence. Transplant. Proc. 2011; 43 (3): 841–846.

Hardinger K.L., Schnitzler M.A., Miller B., et al. Fiveyear follow up of hymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation. 2004; 78 (1): 136–141.

Hardinger K.L., Rhee S., Buchanan P., et al. A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction mmunosuppressive therapy: 10-year results. Transplantation. 2008; 86 (7): 947–952.

Webster A.C., Playford E.G., Higgins G., et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev. 2010; (1): CD003897.

Ciancio G, Burke G.W., Gaynor J.J., et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate 2005; 80 (4): 457-465.

Abou-Ayache R., B chler M., Lepogamp P., et al. CMV infections after two doses of daclizumab versus thymoglobulin in renal transplant patients receiving mycophenolate mofetil, steroids and delayed cyclosporine A. Nephrol. Dial. Transplant. 2008; 23 (6): 2024–2032.

Vincenti F., de Andrés A., Becker T., et al. Interleukin-2 receptor antagonist induction in modern immunosuppression regimens for renal transplant recipients. Transplant Int. 2006; 19 (6): 446–457.

Brennan D.C., Schnitzler M.A. Longterm results of rabbit antithymocyte globulin and basiliximab induction. N. Engl. J. Med. 2008; 359 (16): 1736–1738.

Hardinger K.L., Brennan D.C., Schnitzler M.A. Rabbit antithymocyte globulin is more beneficial in standard kidney than in extended donor recipients. Transplantation. 2009; 87 (9): 1372–1376.

Willoughby L.M., Schnitzler M.A., Brennan D.C., et al. Early outcomes of thymoglobulin and basiliximab induction in kidney transplantation: application ofstatistical approaches to reduce bias in observational comparisons. Transplantation.2009; 87 (10): 1520–1529.

Mehrabi A., Mood Z.A., Sadeghi M., et al. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol. Dial. Transplant. 2007; 22 Suppl. 8: viii54-viii60.

Huang Y., Rabb H., Womer K.L. Ischemia- reperfusion and immediate T-cell responses. Cell. Immunol. 2007; 248 (1): 4–11.

Beiras-Fernandez A., Chappell D., Hammer C., Thein E. Influence of polyclonal antithymocyte globulins upon ischemia–reperfusion injury in a nonhuman primate model. Transplant. Immunol. 2006; 15 (4): 273–279.

Beiras-Fernandez A., Thein E., Chappell D., et al. Polyclonal anti-thymocyte globulins influence apoptosis in reperfused tissues after ischemia in a nonhuman primate model. Transplant. Int. 2004; 17 (8): 453–457.

Mueller T.F. Mechanisms of action of Thymoglobulin. Transplantation. 2007; 84 Suppl. 11: 5–10.

Goggins W.C., Pascual M.A., Powelson J.A., et al. A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients. Transplantation. 2003; 76 (5): 798–802.

Kamar N, Garrigue V, Karras A., et al. Impact of early or delayed cyclosporine on delayed graft function in renal transplant recipients: a randomized, multicenter study. Am. J. Transplant. 2006; 6 (5 Pt. 1): 1042–1048.

Lebranchu Y., Aubert P., Bayle F., et al. Could steroids be withdrawn in renaltransplant patients sequentially treated with ATG, cyclosporine, and cellcept? One-year results of a double-blind, randomized, multicenter study comparing normal dose versus low-dose and withdrawal of steroids. M 55002 French. Study Group. Transplant. Proc. 2000; 32 (2): 396–397.

Woodle E.S., Peddi V.R., Tomlanovich S., et al. Study Investigators. A prospective, randomized, multicenter study evaluating early corticosteroid withdrawal with Thymoglobulin in living-donor kidney transplantation. Clin. Transplant. 2010; 24 (1): 73–83.31. Swanson S.J., Hale D.A., Mannon R.B., et al. Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy. Lancet. 2002; 3609346): 1662–1664.

Grinyó J.M., Gil-Vernet S., Cruzado J.M., et al. Calcineurin inhibitor-free immunosuppression based on antithymocyte globulin and mycophenolate mofetil in cadaveric kidney transplantation: results after 5 years. Transplant. Int. 2003; 16 (11): 820–827.

B chler M., Caillard S., Barbier S., et al. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am. J. Transplant. 2007; 7 (11): 2522–2531.

Lebranchu Y., Snanoudj R., Toupance O., et al. Five-year results of a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation: the Spiesser study. Am. J. Transplant. 2012; 12 (7): 1801–1810.

Glotz D., Charpentier B., Abramovicz D., et al. Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids. Transplant. 2010; 89 (12): 1511–1517.

Ekberg H., Tedesco-Silva H., Demirbas A., et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N. Engl. J. Med. 2007; 357 (25): 2562–2575.

Flechner S.M., Glyda M., Cockfield S., et al. The ORION Study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am. J. Transplant. 2011; 11 (8): 1633–1644.

Thymoglobulin 25 mg powder for solution for infusion: summary of product characteristics. Available at: http:// www.medicines.org.uk/emc/medicine/20799/SPC.

Brennan D.C., Flavin K., Lowell J.A., et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999; 67 (7): 1011–1018.

B chler M., Hurault de Ligny B., Madec C., et al. Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr followup of safety and efficacy. Clin. Transplant. 2003; 17 (6): 539–545.

Tsapepas D., Mohan S., Crew R.J., et al. Small thymoglobulin dose adjustments have profound impact on early rejections in renal transplantation. Am. J. Transplant. 2011; 11 Suppl. 2: 147

Hardinger K.L. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy. 2006; 26 (12): 1771–1783.

Khositseth S., Matas A., Cook M.E., etal. Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplant recipients: a single-center report.Transplantation. 2005; 79 (8): 958–963.

Schwartz J.J., Ishitani M.B., Weckwerth J., et al. Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression. Transplantation. 2007; 84 (6): 715–721.

Brophy P.D., Thomas S.E., Mcbryde K.D., Bunchman T.E. Comparison of polyclonal induction agents in pediatric renal transplantation. Pediatr. Transplant.2001; 5 (3): 174–178

Kamel M.H., Mohan P., Little D.M., et al. Rabbit antithymocyte globulin as induction immunotherapy for pediatric deceased donor kidney transplantation.J. Urol. 2005; 174 (2): 703–707.

Boothpur R., Hardinger K.L., Skelton R.M., et al. Serum sickness after treatment with rabbit antithymocyte globulin in kidney transplant recipients with previous rabbit exposure. Am. J. Kidney Dis. 2010; 55 (1): 141–143.

Issa N., Fishman J.A. Infectious complications of antilymphocyte therapies in solid organ transplantation. Clin. Infect. Dis. 2009; 48 (6): 772–786.

Dadhania D., Snopkowski C., Ding R., et al. Epidemiology of BK virus in renal allograft recipients: independent risk factors for BK virus replication. ransplantation.2008; 86 (4): 521–528.

Srinivas T.R., Schold J., Guerra G., et al. Total rabbit ATG dose is a risk factor for onset of BK viremia in kidney transplant recipients. Am. J. Transplant. 2007;7 Suppl. 2: 235.

Ducloux D., Carron P.L., Motte G., et al. Lymphocyte subsets and assessmentof cancer risk in renal transplant recipients. Transplant. Int. 2002; 15 (8): 393–396.

Glowacki F., Al Morabiti M., Lionet A., et al. Long-term kinetics of a T-lymphocytes subset in kidney transplant recipients: relationship with posttransplant malignancies. Transplant. Proc. 2009; 41 (8): 3323–3325.

Thibaudin D., Alamartine E., Mariat C., et al. Long-term kinetic of T-lymphocyte subsets in kidney-transplant recipients: influence of anti-T-cell antibo dies and association with posttransplant malignancies. Transplantation. 2005; 80 (10): 1514–1517.

The authors declare that there are no conflicts of interest present.