Рецепт. 2020; 24: 39-49
Индукционная иммуносупрессия анти-СD-антителами и иммунологический статус реципиентов почечного трансплантата
https://doi.org/10.34883/PI.2020.23.1.004Аннотация
Цель. Изучить иммунологические показатели у реципиентов почечного трансплантата, получавших базиликсимаб в качестве индукционной иммуносупрессии.
Материалы и методы. У 199 реципиентов почечного аллотрансплантата определяли уровень СD3+, CD3+CD4+, СD3+CD8+, CD19+, CD3-CD16+CD56+, CD3+CD16+CD56-, СD3+HLA-DR+, CD3+СD4+CD25+, CD3+CD8+HLA-DR+, CD3+CD4+HLA-DR+, CD3+CD38+, CD3+CD4+CD25+highCD127+low в периферической крови методом проточной цитофлуометрии перед операцией, на 3-и, 7-е, 30-е, 90-е и 180-е сутки послеоперационного периода. Все пациенты получали индукционную терапию анти-CD25 моноклональными антителами.
Результаты и обсуждение. Выявлены значимые снижения к 3-м суткам Т-лимфоцитов, Т-хелперов и Т-цитотоксических лимфоцитов. Наблюдался рост CD3+ и CD3+CD8+ к 180-м суткам после операции. Уровень Т-хелперов был значимо выше на 90-е сутки, а через 180 суток не отличался от дооперационных показателей. Однако абсолютный уровень Т-хелперов с 90-х по 180-е сутки снижался, не достигнув дооперационного показателя. Отмечен значимый рост относительного уровня В-лимфоцитов на 3-и сутки после операции с уменьшением к 180-му дню. На 3-и сутки отмечено значимое снижение относительного и абсолютного уровня CD3+CD16+CD56+ и CD3-CD16+CD56+ с последующим значимым ростом к 180-м суткам.
Выявлено снижение относительного уровня активированных лимфоцитов на 3-и сутки всех субпопуляций, кроме CD3+CD8+HLA-DR+, количество которых значимо увеличивалось до 180-х суток. Однако CD3+CD38+ и CD3+CD4+HLA-DR+ снижались в течение 6 месяцев. Динамика относительного уровня Т-хелперов и Т-регуляторных лимфоцитов характеризовалась значимым снижением к 3-м суткам, минимальными значениями на протяжении месяца с восстановлением дооперационных показателей к 3-му месяцу. Абсолютные показатели всех изучаемых активированных лимфоцитов характеризовались значимым снижением на 3-и сутки с восстановлением к 90-м суткам. Наблюдался значимый рост к 6-му месяцу уровня CD3+HLA-DR+, CD3+CD8+HLA-DR+, CD3+CD4+CD25+ и CD3+CD4+CD25+highCD127+low.
Заключение. Блокировка рецептора интерлейкина-2 на лимфоцитах наблюдается на протяжении 3 месяцев, что необходимо учитывать при оценке результатов иммунологического мониторинга реципиентов почечного трансплантата, получающих анти-СD-антитела в качестве индукционной иммуносупрессивной терапии. В следующих наших публикациях мы представим показатели иммунологического статуса реципиентов почечного трансплантата в зависимости от группы лекарственных средств, используемых в качестве индукционной иммуносупрессии.
Список литературы
1. Hart A., Smith J.M., Skeans M.A., Gustafson S.K., Wilk A.R., Castro S., Foutz J., Wainright J.L., Snyder J.J., Kasiske B.L., Israni A.K. (2020) OPTN/SRTR 2018 Annual Data Report: Kidney. United States organ transplantation, vol. 20, Iss. 1, pp. 20–130.
2. Opelz G., Döhler B. (2009) Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation. vol. 87, no 6, pp. 795–802.
3. Tian J.H., Wang X., Yang K.H., Liu A.P., Luo X.F., Zhang J. (2009) Induction with and without antithymocyte globulin combined with cyclosporine/tacrolimus-based immunosuppression in renal transplantation: a meta-analysis of randomized controlled trials. Transplant Proc., vol. 41, no 9, pp. 3671–6.
4. Webster A.C., Ruster L.P., McGee R., Matheson S.L., Higgins G.Y., Willis N.S., Chapman J.R., Craig J.C. (2010) Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev., vol. 1, pp. 250.
5. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. (2009) KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J. Transplant., vol. 9, pp. 1–155.
6. Hellemans R., Bosmans J.L., Abramowicz D. (2017) Induction therapy for kidney transplant recipients: Do we still need anti-IL2 receptor monoclonal antibodies? Am J. Transplant., vol. 17, no 1, pp. 22–27.
7. Kretschmer K., Apostolou I., Hawiger D., Khazaie K., Nussenzweig M.C., Von Boehmer H. (2005) Inducing and expanding regulatory t cell populations by foreign antigen. Nat. Immunol., vol. 6, pp. 1219–27.
8. Veronese F., Rotman S., Smith R.N., Pelle T.D., Farrell M.L., Kawai T., Benedict Cosimi A., Colvin R.B. (2007) Pathological and clinical correlates of FOXP3+ cells in renal allografts during acute rejection. Am J. Transplant., vol. 7, no 4, pp. 914–22.
9. Velthuis J.H., Mol W.M., Weimar W., Baan C.C. (2006) CD4+CD25bright+ Regulatory T cells can mediate donor nonreactivity in long-term immunosuppressed kidney allograft patients. Am J. Transplant., vol. 6, pp. 2955–64.
10. Malek T.R., Yu A., Vincek V., Scibelli P., Kong L. (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2R beta-defcient mice. Implications for the nonredundant function of IL-2. Immunity; vol. 17, pp. 167–78.
11. Sadlack B., Merz H., Schorle H., Schimpl A., Feller A.C., Horak I. (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell., vol. 75, pp. 253–61.
12. Wang Z., Xiao L., Shi B.Y., Qian Y.Y., Bai H.W., Chang J.Y., Cai M. (2008) Short-term anti-CD25 monoclonal antibody treatment and neogenetic CD4(+)CD25(high) regulatory T cells in kidney transplantation. Transpl Immunol., vol. 19, pp. 69–73.
Recipe. 2020; 24: 39-49
Induction Immunosupression with Anti-CD Antibodies and Immune Status of Kidney Transplant Recipients
https://doi.org/10.34883/PI.2020.23.1.004Abstract
Objective. To study immunological parameters in kidney transplant recipients who received basiliximab as induction immunosuppression.
Materials and methods. In 199 renal allograft recipients, the levels of СD3+, CD3+CD4+, СD3+CD8+, CD19+, CD3-CD16+CD56+, CD3+CD16+CD56-, СD3+HLA-DR+, CD3+СD4+CD25+, CD3+CD8+HLA-DR+, CD3+CD4+HLA-DR+, CD3+CD38+, CD3+CD4+CD25+highCD127+low were determined in peripheral blood by flow cytometry before surgery, on the 3rd, 7th, 30th, 90th and 180th day of the postoperative period. All patients received induction therapy with anti-CD25 monoclonal antibodies.
Results and discussion. Were revealed signifcant decreases of T-lymphocytes, T-helpers and cytotoxic T-lymphocytes by the 3rd day. There was an increase in CD3+ and CD3+CD8+ by the 180th day after surgery. The level of T-helpers was signifcantly higher on the 90th day, and it did not differ from preoperative indices after 180 days. However, the absolute level of T-helpers from the 90th to the 180th days decreased, it has not reached the presurgery signifcative. There was noted a signifcant increase in the relative level of B-lymphocytes on the 3rd day after surgery with a decrease by the 180th day. There was noted on the 3rd day, a signifcant decrease in the relative and absolute levels of CD3+CD16+CD56+ and CD3-CD16+CD56+, followed by a signifcant increase by the 180th day. There was detected a decrease in the relative level of activated lymphocytes on the 3rd day of all subpopulations except for CD3+CD8+HLA-DR+, which signifcantly increased up to 180 days.
However, CD3+CD38+ and CD3+CD4+HLA-DR+ decreased for 6 months. The dynamics of the relative level of T-helpers and T-regulatory lymphocytes was characterized by a signifcant decrease by the 3rd day, the minimum values during the month with the restoration of preoperative parameters by the 3rd month. The absolute values of all studied activated lymphocytes were characterized by a signifcant decrease on the 3rd day with recovery by the 90th day. By the 6th month, there was a signifcant increase in the levels of CD3+HLA-DR+, CD3+CD8+HLA-DR+, CD3+CD4+CD25+ and CD3+CD4+CD25+highCD127+low.
Conclusions.There is observed the Interleukin-2 receptor blocking on lymphocytes for three months, which must be taken into account when evaluating the results of immunological monitoring of kidney transplant recipients receiving anti-CD antibodies as induction immunosuppressive therapy.
In our next publications, we will present the immunological status of kidney transplant recipients, depending on the group of drugs used as induction immunosuppression.
References
1. Hart A., Smith J.M., Skeans M.A., Gustafson S.K., Wilk A.R., Castro S., Foutz J., Wainright J.L., Snyder J.J., Kasiske B.L., Israni A.K. (2020) OPTN/SRTR 2018 Annual Data Report: Kidney. United States organ transplantation, vol. 20, Iss. 1, pp. 20–130.
2. Opelz G., Döhler B. (2009) Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation. vol. 87, no 6, pp. 795–802.
3. Tian J.H., Wang X., Yang K.H., Liu A.P., Luo X.F., Zhang J. (2009) Induction with and without antithymocyte globulin combined with cyclosporine/tacrolimus-based immunosuppression in renal transplantation: a meta-analysis of randomized controlled trials. Transplant Proc., vol. 41, no 9, pp. 3671–6.
4. Webster A.C., Ruster L.P., McGee R., Matheson S.L., Higgins G.Y., Willis N.S., Chapman J.R., Craig J.C. (2010) Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev., vol. 1, pp. 250.
5. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. (2009) KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J. Transplant., vol. 9, pp. 1–155.
6. Hellemans R., Bosmans J.L., Abramowicz D. (2017) Induction therapy for kidney transplant recipients: Do we still need anti-IL2 receptor monoclonal antibodies? Am J. Transplant., vol. 17, no 1, pp. 22–27.
7. Kretschmer K., Apostolou I., Hawiger D., Khazaie K., Nussenzweig M.C., Von Boehmer H. (2005) Inducing and expanding regulatory t cell populations by foreign antigen. Nat. Immunol., vol. 6, pp. 1219–27.
8. Veronese F., Rotman S., Smith R.N., Pelle T.D., Farrell M.L., Kawai T., Benedict Cosimi A., Colvin R.B. (2007) Pathological and clinical correlates of FOXP3+ cells in renal allografts during acute rejection. Am J. Transplant., vol. 7, no 4, pp. 914–22.
9. Velthuis J.H., Mol W.M., Weimar W., Baan C.C. (2006) CD4+CD25bright+ Regulatory T cells can mediate donor nonreactivity in long-term immunosuppressed kidney allograft patients. Am J. Transplant., vol. 6, pp. 2955–64.
10. Malek T.R., Yu A., Vincek V., Scibelli P., Kong L. (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2R beta-defcient mice. Implications for the nonredundant function of IL-2. Immunity; vol. 17, pp. 167–78.
11. Sadlack B., Merz H., Schorle H., Schimpl A., Feller A.C., Horak I. (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell., vol. 75, pp. 253–61.
12. Wang Z., Xiao L., Shi B.Y., Qian Y.Y., Bai H.W., Chang J.Y., Cai M. (2008) Short-term anti-CD25 monoclonal antibody treatment and neogenetic CD4(+)CD25(high) regulatory T cells in kidney transplantation. Transpl Immunol., vol. 19, pp. 69–73.
