Multipl miyelom’da CD4+ regülatör T hücrelerin rolü

Deniz Ekinci; Aysun Özkan

doi:10.17826/cutf.323972

Derleme

Multipl miyelom’da CD4+ regülatör T hücrelerin rolü

Yıl 2017, Cilt: 42 Sayı: 3, 546 - 551, 30.09.2017

Deniz Ekinci Aysun Özkan

https://doi.org/10.17826/cutf.323972

Öz

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.

Anahtar Kelimeler

PD-1/PDL1-PDL2, Multipl miyelom, regülatör T hücreler, PD-1/PDL1-PDL2

Kaynakça

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

Yıl 2017, Cilt: 42 Sayı: 3, 546 - 551, 30.09.2017

Deniz Ekinci Aysun Özkan

https://doi.org/10.17826/cutf.323972

Öz

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.

Anahtar Kelimeler

PD-1/PDL1-PDL2, Multiple myeloma, regulatory T cells, PD-1/PDL1-PDL2

Kaynakça

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.

Toplam 44 adet kaynakça vardır.

Ayrıntılar

Konular	Sağlık Kurumları Yönetimi
Bölüm	Derleme
Yazarlar	Deniz Ekinci Bu kişi benim Aysun Özkan
Yayımlanma Tarihi	30 Eylül 2017
Gönderilme Tarihi	8 Şubat 2107
Kabul Tarihi	16 Mart 2017
Yayımlandığı Sayı	Yıl 2017 Cilt: 42 Sayı: 3

Kaynak Göster

MLA	Ekinci, Deniz ve Aysun Özkan. “Multipl miyelom’da CD4+ regülatör T hücrelerin Rolü”. Cukurova Medical Journal, c. 42, sy. 3, 2017, ss. 546-51, doi:10.17826/cutf.323972.

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