POSSIBLE MECHANISMS OF STIMULATORY EFFECTS OF MESENCHYMAL STROMAL CELLS UPON T CELL RECOVERY DURING CHEMOTHERAPY-INDUCED LYMPHOPENIA

The aim of present work was to evaluate the effect of mesenchymal stromal cells (MSCs) from lymphoma patients on the in vitro and in vivo homeostatic proliferation of lymphocytes. Our data have demonstrated
for the first time, that MSCs from lymphoma patient are able to enhance the in vitro proliferation of donor and patient mononuclear cells (MNCs) in response to IL-2 or IL-7. This effect was observed within a wide range
of MSC-to-MNC ratios (1:50-1:2). Lymphocyte reactivity to IL-2 or IL-7 was found to be an important factor determining the stimulatory effect of MSCs. Ex vivo studies in the patients undergoing autologous hematopoietic stem cell transplantation (AHSCT) have shown that the patients co-transplanted with MSCs exhibited higher proportions of proliferating CD8+T cells (especially, memory cells) at the day of engraftment, than before AHSCT, as compared to the patients subjected to standard AHSCT protocols. Moreover, there was no an increase in apoptosis of naive CD4+T cells that was typical for standard AHSCT. These data indicate that the stimulatory effect of MSCs upon T lymphocyte proliferation following chemotherapy-induced lymphopenia
concerns, mainly, the memory CD8+T cell population, whereas more efficient recovery of naive CD4+T cells is due to anti-apoptotic effects of MSCs.

1. Chernykh E.R., Batorov E.V., Shevela E.Ya., Pronkina N.V., Kryuchkova I.V., Sergeevicheva V.V., Gilevich A.V., Baranova D.S., Kozhevnikov V.S., Ostanin A.A. Vliyanie mezenkhimal`nykh stromal`nykh kletok na rannee vosstanovlenie T-limfotsitov u bol`nykh zlokachestvennymi limfomami s autologichnoy transplantatsiey gemopoeticheskikh stvolovykh kletok [Effect of mesenchymal stromal cells on the early reconstitution of T-lymphocytes in malignant lymphoma patients with autologous hematopoietic stem cell transplantation]. Immunologiya – Immunology, 2013, vol. 34, no. 4, pp. 202-207.

2. Chernykh E.R., Batorov E.V., Shevela E.Ya., Pronkina N.V., Sergeevicheva V.V., Gilevich A.V., Baranova D.S., Ostanin A.A., Kryuchkova I.V. Vliyanie mezenkhimal`nykh stromal`nykh kletok na rannee vosstanovlenie limfotsitov u bol`nykh zlokachestvennymi limfomami s autologichnoy transplantatsiey gemopoeticheskikh stvolovykh kletok [Effect of mesenchymal stromal cells on the early lymphocyte recovery in patients receiving autologous hematopoietic stem cell transplantation for malignant lymphomas]. Byulleten` SO RAMN – Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences, 2011, vol. 31, no. 2, pp. 101-107.

3. Shevela E.Ya., Petrovskiy Ya.L., Kurganova E.V., Tikhonova M.A., Sakhno L.V., Sergeevicheva V.V., Kulagin A.D., Lisukov I.A., Ostanin A.A., Chernykh E.R. Harakteristika mezenkhimal`nykh stromal`nykh kletok kostnogo mozga u bol`nykh gemoblastozami [Characteristics of bone marrow mesenchymal stromal cells in patients with hematological malignancies]. Gematologiya i transfuziologiya – Haematology and Transfusiology, 2008, no. 2, pp. 32-38.

4. Ball L.M., Bernardo M.E., Roelofs H., Lankester A., Cometa A., Egeler R.M., Locatelli F., Fibbe W.E. Co-transplantation of ex vivo-expanded mesenchymal stem cells accelerates lymphocytes recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem cell transplantation. Blood, 2007, vol. 110, pp. 2764-2767.

5. Ben-Ami E., Berrih-Akhin S., Miller A. Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases. Autoimmun. Rev., 2011, vol. 10, no. 7, pp. 410-405.

6. Bocelli-Tyndall С., Bracci L., Schaeren S., Feder-Mengus C., Barbero A., Tyndall A., Spagnoli G.C. Human bone marrow mesenchymal stem cells and chondrocytes promote and/or suppress the in vitro proliferation of lymphocytes stimulated by interleukins 2, 7 and 15. Ann. Rheum. Dis., 2009, vol. 68, pp. 1352- 1359.

7. Bocelli-Tyndall C., Bracci L., Spagnoli G., Braccini A., Bouchenaki M., Ceredig R., Pistoia V., Martin I., Tyndall A. Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and autoimmune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro. Rheumatology (Oxford), 2007, vol. 46, no. 3, pp. 403-408.

8. Boyman O., Létourneau S., Kreig C., Sprent J. Homeostatic proliferation and survival of na ve and memory T cells. Eur. J. Immunol., 2009, vol. 39, no. 8, pp. 2088-2094.

9. Caplan A.I., Dennis J.E. Mesenchymal stem cells as trophic mediators. J. Cell Biochem., 2006, vol. 98, pp. 1076-1084.

10. Cho J.H., Boyman O., Kim H.O., Hahm B., Rubinstein M.P., Ramsey C., Kim D.M., Surh C.D., Sprent J. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J. Exp. Med., 2007, vol. 204, no. 8, pp. 1787-1801.

11. Crop M.J., Baan C.C., Korevaar S.S., Ijzermans J.N., Weimar W., Hoogduijn M.J. Human adipose tissue-derived mesenchymal stem cells induce explosive T-cell proliferation. Stem Cells Dev., 2010, vol. 19, no. 12, pp. 1843-1853.

12. Fekete N., Gadelorge M., F rst D., Maurer C., Dausend J., Fleury-Cappellesso S., Mail nder V., Lotfi R., Ignatius A., Senseb L., Bourin P., Schrezenmeier H., Rojewski M.T. Platelet lysate from whole blood-derived pooled platelet concentrates and apheresis-derived platelet concentrates for the isolation and expansion of human bone marrow mesenchymal stromal cells: production process, content and identification of active components. Cytotherapy, 2012, vol. 14, no. 5, pp. 540-554.

13. Fry T.J., Connick E., Fallon J., Lederman M.M., Liewehr D.J., Spritzler J., Steinberg S.M., Wood L.V., Yarchoan R., Zuckerman J., Landay A., Mackall C.L. A potential role for interleukin-7 in T-cell homeostasis. Blood, 2001, vol. 97, no. 10, pp. 2983-2990.

14. Isaikina Y., Minakovskaya N., Aleinikova O. The influence of autologous marrow mesenchymal stem cell infusion on hematopoiesis reconstitution after hematopoietic stem cells autotransplantation in children with oncological and hematological diseases. Cellular Therapy and Transplantation, 2008, vol. 1, no. 1, pp. 35-42.

15. Kamimura D., Bevan M.J. Naive CD8+ T cells differentiate into protective memory-like cells after IL-2 anti IL-2 complex treatment in vivo. J. Exp. Med., 2007, vol. 204, no. 8, pp. 1803-1812.

16. Kim J., Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp. Hematol., 2009, vol. 37, pp. 1445-1453.

17. Le Blanc K., Samuelsson H., Gustafsson B., Remberger M., Sundberg B., Arvidson J., Ljungman P., L nnies H., Nava S., Ringdén O. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia, 2007, vol. 21, no. 8, pp. 1733-1738.

18. Le Blanc K., Tammik L., Sundberg B., Haynesworth S.E., Ringdén O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand. J. Immunol., 2003, vol. 57, pp. 11-20.

19. Li W., Ren G., Huang Y., Su J., Han Y., Li J., Chen X., Cao K., Chen Q., Shou P., Zhang L., Yuan Z.R., Roberts A.I., Shi S., Le A.D., Shi Y. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death & Differentiation, 2012, vol. 19, pp. 1505-1513.

20. Mackall C.L, Hakim F.T., Gress R.E. Restoration of T-cell homeostasis after T-cell depletion. Immunology, 1997, vol. 9, pp. 339-346.

21. Najar M., Rouas R., Raicevic G., Boufker H.I., Lewalle P., Meuleman N., Bron D., Toungouz M., Martiat P., Lagneaux L. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy, 2009, vol. 11, no. 5, pp. 570-583.

22. Sergeevicheva V.V., Shevela E.Ya., Sizikova S.A., Kulagin A.D., Kruchkova I.V., Gilevich A,V., Lisukov I.A., Kozlov V.A., Ostanin A.A., Chernykh E.R. Autologous mesenchymal stromal cells of hemoblastoses patients efficiently support hematopoietic recovery stem cell transplantation. Cellular Therapy and Transplantation, 2010, vol. 1, no. 4, pp. 98-105.

23. Shevela E.Ya., Tikhonova M.A., Batorov E.V., Sergeevicheva V.V., Kryuchkova I.V., Kozlov V.A., Ostanin A.A., Chernykh E.R. Impaired Functions of Bone Marrow Mesenchymal Stromal Cells in Patients with Hematological Malignancies are Partially Improved by Fibroblast Growth Factor. J. Stem. Cell Res. Ther., 2013, vol. 3:137. doi: 10.4172/2157-7633.1000137.

24. Sprent J., Surh C.D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol., 2011, vol. 12, no. 6, pp. 478-484.