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Multipl miyelom’da CD4+ regülatör T hücrelerin rolü

Year 2017, Volume: 42 Issue: 3, 546 - 551, 30.09.2017
https://doi.org/10.17826/cutf.323972

Abstract

Yapılan pek çok araştırmada hem yeni tanı multipl miyelomda hem de otolog kök hücre nakli dahil kemoterapötik tedaviler sonrası hastalarda regülatör T hücrelerin artışı söz konusudur. Multipl miyelom habis bir plazma hücre hastalığıdır. Regülatör T hücreleri kanser ve inflamatuar koşullardan otoimmün hastalıklara kadar immün homeostazide rol oynar. PD-1 yolağı yardımcı T hücre popülasyonunu regülatör T hücre gelişimi yönünde uyarmaktadır. PDL1'in indüklenebilir regülatör T hücrelerin farklılaştırılmasında önemli bir rol oynadığı gösterilmiştir. Son zamanlarda multipl miyelomda PDL1 veya PD-1'i hedef alan en az altı klinik çalışma başlatılmıştır. Mevcut literatüre göre miyelom hastalarının anti PD-1/PDL1 tedavisinden fayda sağlayabileceğini önermekteyiz.

References

  • 1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962–72.
  • 2. Raja KRM, Kubiczkova L, Rihova L, Piskacek M, Vsianska P, Hezova R et al. Functionally suppressive cd8 t regulatory cells are increased in patients with multiple myeloma: a cause for immune impairment. PLoS One. 2012;7:e49446.
  • 3. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-73.
  • 4. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clinic Proc. 1975;50:29-40.
  • 5. Kyle RA, Gertz MA, Witzing TE, Lust JA, Lacy MQ, Dispenzieri A et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc. 2003;78:21-33.
  • 6. Türk Hematoloji Derneği. Hematolog. Multipl Miyelom. 2013;3:32-3. 7. Raja KRM, Kovarova L, Hajek R. Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders. Br J Haematol. 2010;149:334-51.
  • 8. Joshua DE, Brown RD, Ho PJ, Gibson J. Regulatory T cells and multiple myeloma. Clin Lymphoma Myeloma. 2008;8:283-6.
  • 9. Belkaid Y. Regulatory T cells and infections: a dangerous necessity. Nat Rev Immunol. 2007;7:875-88.
  • 10. Akdis CA, Blaser K. Bypassing IgE and targeting T cells for specific immunotherapy of allergy. Trends Immunol. 2001;22:175-8.
  • 11. Akdis CA, Blesken T, Akdis M, Wu TB, Blaser K. Role of IL-10 in specific immunotherapy. J Clin Invest. 1998;102:98-106.
  • 12. Lıanjun Z, Yong Z. The regulation of FoxP3 Expression in regulatory CD4+CD25+ T cells: multiple pathways on the road. J Cell Physiol. 2007;211:590-7.
  • 13. Mantel PY, Ouaked N, Rückert B, Karagiannidis C, Welz R, Blaser K et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol. 2006;176:3593-3602.
  • 14. Ziegler SF, Buckner JH. FOXP3 and the regulation of Treg/Th17 differentiation. Microbes Infect. 2009;11:594-8.
  • 15. Başkan EB. T hücre immünitesi. Türkderm-Deri Hastalıkları ve Frengi Arşivi Dergisi. 2013;47 (Özel Sayı 1):18-23. 16. Mays LE, Chen YH. Maintaining immunological tolerance with Foxp3. Cell Res. 2007;17:904-18.
  • 17. Hori S, Nomura T, Sakaquchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;14:299:1057-61.
  • 18. Chess L. The birth of functionally distinct T cell subsets. J Immunol. 2006;176:3859-60.
  • 19. Jiang H, Chess L. Regulation T cells-teh renaissance of the suppressor T cells. Ann Med. 2007;39:322-34.
  • 20. Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur J Immunol. 2002;32:1621-30.
  • 21. Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol. 1999;162:5317-26.
  • 22. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD et al. Human CD4(+)CD25(+) cells: a naturally occuring population of regulatory T cells. Blood. 2001;98:2736-44.
  • 23. Miyaral M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007;13:108-15.
  • 24. Braga WMT, Silva BR, Carvalho AC, Maekawa YH, Bortoluzzo AB, Rizzatti EG et al. Foxp3 and Ctla4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4+ T regulatory cells. Cancer Immunol Immunother. 2014;63:1189–97.
  • 25. Braga WMT, Atanackovic D, Colleoni GWB. The Role of regulatory T cells and TH17 cells in multiple myeloma. Clin Dev Immunol. 2012;2012:293479.
  • 26. Udagawa T, Narumi K, Suzuki K, Aida K, Miyakawa R, Ikarashi Y et al. Vascular endothelial growth factor-D-mediated blockade of regulatory T cells within tumors is induced by hematopoietic stem cell transplantation. J Immunol. 2013;191:3440-52.
  • 27. Feng P, Yan R, Dai X, Xie X, Wen H, Yang S. The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma. Inflammation. 2015;38:705-9.
  • 28. Ganeshan P, Gupta R, Hakim M, Kumar L, Bhaskar A, Sharma A. Reconstitution of regulatory T cells after autologous transplantation in multiple myeloma. Int J Hematol. 2011;94:578-9.
  • 29. Raja KRM, Hajek R. Contribution of regulatory T cells to immunosuppression and disease progression in multiple myeloma patients. Oncoimmunology. 2013;2:e25619.
  • 30. Raja KRM, Rihova L, Zahradova L, Klincova M, Penka M, Hajek R. Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma. PLoS One. 2012;7:e47077.
  • 31. Giannopoulos K, Kaminska W, Hus I. and Dmoszynska A. The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterization of immune status in multiple myeloma. Br J Cancer. 2012;106:546-52.
  • 32. Erçetin AP, Aktaş S, Pişkin Ö, Özcan MA. Multipl miyelomda Galektin-1 ekspresyonunun düzenleyici T hücreler ve otolog kemik iliği transplantasyonu ile ilişkisi. Dokuz Eylül Üniversitesi Tıp Fakültesi Dergisi. 2011;25:137-43.
  • 33. Erçetin AP, Aktaş S, Pişkin Ö, Ateş H, Zadeoğluları ZF, Turgut NH et al. Multipl miyelomda T düzenleyici hücreleri ile otolog çevre kanı kök hücre nakli arasındaki korelasyonun araştırılması. Turk J Haematol. 2011;28:107-14.
  • 34. Ates A, Ilhan O, Ozcan M, Dalva K, Ugur N, Beksac M et al. T-cell subsets in multiple myeloma: relation to clinical phase and stage of disease and prognosis. Blood. 1998;92:260B.
  • 35. Özer H, Han T, Henderson ES, Nussbaum A, Sheedy D. Immunoregulatory T cell function in multiple myeloma. J Clin Invest. 1981;67:779-89.
  • 36. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887-95.
  • 37. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8.
  • 38. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co- stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-9.
  • 39. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193:839-46.
  • 40. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp Med. 2000;192:1027-34.
  • 41. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883-95.
  • 42. Scandiuzzi L, Ghosh K, Hofmeyer KA, Abadi YM, Lázár-Molnár E, Lin EY et al. Tissue-expressed B7-H1 critically controls intestinal inflammation. Cell Rep. 2014;6:625-32.
  • 43. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110:296-304.
  • 44. Ray A, Das DS, Song Y, Richardson P, Munshi NC, Chauhan D et al. Targeting PD1-PDL1 immune check-point in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia. 2015;29:1441-4.
  • 45. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015-29.
  • 46. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3—potential mechanisms of action. Nat Rev Immunol. 2015;15:45-56.

Role of CD4+ regulatory T cells in multiple myeloma

Year 2017, Volume: 42 Issue: 3, 546 - 551, 30.09.2017
https://doi.org/10.17826/cutf.323972

Abstract

In many studies, regulatory T cell increase is seen both in patients with newly diagnosed multiple myeloma and post chemotherapy patients including autologous stem cell transplants. Multiple myeloma is a malignant plasma cell disease. Regulatory T cells have a role in immune homeostasis from cancer and inflamatory conditions to autoimmune diseases. PD-1 pathway stimulates T cell population towards regulatory T cell development. It has been shown that PDL1 plays an important role in differentiating inducable regulatory T cells. Recently, at least six clinical studies targeting PDL1 or PD-1 on multiple myeloma have been started. In accordance with the current literature, we suggest that patients with myeloma can benefit anti PD-1/PDL1 therapy.

References

  • 1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962–72.
  • 2. Raja KRM, Kubiczkova L, Rihova L, Piskacek M, Vsianska P, Hezova R et al. Functionally suppressive cd8 t regulatory cells are increased in patients with multiple myeloma: a cause for immune impairment. PLoS One. 2012;7:e49446.
  • 3. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-73.
  • 4. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clinic Proc. 1975;50:29-40.
  • 5. Kyle RA, Gertz MA, Witzing TE, Lust JA, Lacy MQ, Dispenzieri A et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc. 2003;78:21-33.
  • 6. Türk Hematoloji Derneği. Hematolog. Multipl Miyelom. 2013;3:32-3. 7. Raja KRM, Kovarova L, Hajek R. Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders. Br J Haematol. 2010;149:334-51.
  • 8. Joshua DE, Brown RD, Ho PJ, Gibson J. Regulatory T cells and multiple myeloma. Clin Lymphoma Myeloma. 2008;8:283-6.
  • 9. Belkaid Y. Regulatory T cells and infections: a dangerous necessity. Nat Rev Immunol. 2007;7:875-88.
  • 10. Akdis CA, Blaser K. Bypassing IgE and targeting T cells for specific immunotherapy of allergy. Trends Immunol. 2001;22:175-8.
  • 11. Akdis CA, Blesken T, Akdis M, Wu TB, Blaser K. Role of IL-10 in specific immunotherapy. J Clin Invest. 1998;102:98-106.
  • 12. Lıanjun Z, Yong Z. The regulation of FoxP3 Expression in regulatory CD4+CD25+ T cells: multiple pathways on the road. J Cell Physiol. 2007;211:590-7.
  • 13. Mantel PY, Ouaked N, Rückert B, Karagiannidis C, Welz R, Blaser K et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol. 2006;176:3593-3602.
  • 14. Ziegler SF, Buckner JH. FOXP3 and the regulation of Treg/Th17 differentiation. Microbes Infect. 2009;11:594-8.
  • 15. Başkan EB. T hücre immünitesi. Türkderm-Deri Hastalıkları ve Frengi Arşivi Dergisi. 2013;47 (Özel Sayı 1):18-23. 16. Mays LE, Chen YH. Maintaining immunological tolerance with Foxp3. Cell Res. 2007;17:904-18.
  • 17. Hori S, Nomura T, Sakaquchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;14:299:1057-61.
  • 18. Chess L. The birth of functionally distinct T cell subsets. J Immunol. 2006;176:3859-60.
  • 19. Jiang H, Chess L. Regulation T cells-teh renaissance of the suppressor T cells. Ann Med. 2007;39:322-34.
  • 20. Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur J Immunol. 2002;32:1621-30.
  • 21. Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol. 1999;162:5317-26.
  • 22. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD et al. Human CD4(+)CD25(+) cells: a naturally occuring population of regulatory T cells. Blood. 2001;98:2736-44.
  • 23. Miyaral M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007;13:108-15.
  • 24. Braga WMT, Silva BR, Carvalho AC, Maekawa YH, Bortoluzzo AB, Rizzatti EG et al. Foxp3 and Ctla4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4+ T regulatory cells. Cancer Immunol Immunother. 2014;63:1189–97.
  • 25. Braga WMT, Atanackovic D, Colleoni GWB. The Role of regulatory T cells and TH17 cells in multiple myeloma. Clin Dev Immunol. 2012;2012:293479.
  • 26. Udagawa T, Narumi K, Suzuki K, Aida K, Miyakawa R, Ikarashi Y et al. Vascular endothelial growth factor-D-mediated blockade of regulatory T cells within tumors is induced by hematopoietic stem cell transplantation. J Immunol. 2013;191:3440-52.
  • 27. Feng P, Yan R, Dai X, Xie X, Wen H, Yang S. The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma. Inflammation. 2015;38:705-9.
  • 28. Ganeshan P, Gupta R, Hakim M, Kumar L, Bhaskar A, Sharma A. Reconstitution of regulatory T cells after autologous transplantation in multiple myeloma. Int J Hematol. 2011;94:578-9.
  • 29. Raja KRM, Hajek R. Contribution of regulatory T cells to immunosuppression and disease progression in multiple myeloma patients. Oncoimmunology. 2013;2:e25619.
  • 30. Raja KRM, Rihova L, Zahradova L, Klincova M, Penka M, Hajek R. Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma. PLoS One. 2012;7:e47077.
  • 31. Giannopoulos K, Kaminska W, Hus I. and Dmoszynska A. The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterization of immune status in multiple myeloma. Br J Cancer. 2012;106:546-52.
  • 32. Erçetin AP, Aktaş S, Pişkin Ö, Özcan MA. Multipl miyelomda Galektin-1 ekspresyonunun düzenleyici T hücreler ve otolog kemik iliği transplantasyonu ile ilişkisi. Dokuz Eylül Üniversitesi Tıp Fakültesi Dergisi. 2011;25:137-43.
  • 33. Erçetin AP, Aktaş S, Pişkin Ö, Ateş H, Zadeoğluları ZF, Turgut NH et al. Multipl miyelomda T düzenleyici hücreleri ile otolog çevre kanı kök hücre nakli arasındaki korelasyonun araştırılması. Turk J Haematol. 2011;28:107-14.
  • 34. Ates A, Ilhan O, Ozcan M, Dalva K, Ugur N, Beksac M et al. T-cell subsets in multiple myeloma: relation to clinical phase and stage of disease and prognosis. Blood. 1998;92:260B.
  • 35. Özer H, Han T, Henderson ES, Nussbaum A, Sheedy D. Immunoregulatory T cell function in multiple myeloma. J Clin Invest. 1981;67:779-89.
  • 36. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887-95.
  • 37. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8.
  • 38. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co- stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-9.
  • 39. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193:839-46.
  • 40. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp Med. 2000;192:1027-34.
  • 41. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883-95.
  • 42. Scandiuzzi L, Ghosh K, Hofmeyer KA, Abadi YM, Lázár-Molnár E, Lin EY et al. Tissue-expressed B7-H1 critically controls intestinal inflammation. Cell Rep. 2014;6:625-32.
  • 43. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110:296-304.
  • 44. Ray A, Das DS, Song Y, Richardson P, Munshi NC, Chauhan D et al. Targeting PD1-PDL1 immune check-point in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia. 2015;29:1441-4.
  • 45. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015-29.
  • 46. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3—potential mechanisms of action. Nat Rev Immunol. 2015;15:45-56.
There are 44 citations in total.

Details

Subjects Health Care Administration
Journal Section Review
Authors

Deniz Ekinci This is me

Aysun Özkan

Publication Date September 30, 2017
Submission Date February 8, 2107
Acceptance Date March 16, 2017
Published in Issue Year 2017 Volume: 42 Issue: 3

Cite

MLA Ekinci, Deniz and Aysun Özkan. “Role of CD4+ Regulatory T Cells in Multiple Myeloma”. Cukurova Medical Journal, vol. 42, no. 3, 2017, pp. 546-51, doi:10.17826/cutf.323972.