Çocukluk Çağı Akut Lenfoblastik Lösemisinde Radyoterapi Doğal Öldürücü Hücre Fonksiyonlarını Artırır Mı?
Öz
Amaç: Bu çalışmanın amacı, akut lenfoblastik lösemili (ALL) çocuklarda tedavi sırasında ve sonrasında doğal öldürücü (NK) hücre oranı, NK hücre aktivitesi ve sitokin düzeylerindeki değişiklikleri araştırmaktır. Gereç ve Yöntem: Çalışma grubu 33 ALL hastasını ve kontrol grubu 11 sağlıklı çocuktan oluştu. ALL hastaları, M protokolünü tamamlayan, idame kemoterapisi alan ve kemoterapisi kesilen olmak üzere üç gruba ayrıldı. NK hücre sitotoksisitesi, farklı efektör-hedef (E:H) hücre oranlarında ve litik birimlerde (LU) değerlendirildi. CD56, CD3, NKp46, CD2, CD94, NKG2D ve CD16 moleküllerinin ekspresyonu ve interferon gamma (IFN-γ) ve interlökin-15 (IL-15) seviyeleri ölçüldü. Bulgular: 1:1 E:H oranında NK hücre aktivitesi idame kemoterapisi alan hastalarda diğer gruplara göre daha yüksek (p<0.05), ancak litik birimler açısından değerlendirildiğinde gruplar arasında fark saptanmadı (p>0.05). CD16+CD56+ hücrelerin oranı, kontrollere göre idame kemoterapi grubunda daha düşük (p<0.05), profilaktik kraniyal radyoterapi uygulanan hastaların 1:1 E:H oranında NK sitotoksisitesi ise almayanlara göre anlamlı olarak daha yüksek saptandı (p<0.05). İdame kemoterapi grubundaki hastaların %83’üne profilaktik kraniyal ışınlama uygulandı. IFN-γ seviyeleri kontrol grubuna göre idame kemoterapi ve tedavi kesilen gruplarda anlamlı olarak daha düşük saptandı (p<0.05). Sonuç: ALL'li çocuklarda kemoterapi NK hücre sayısını ve IFN-γ düzeylerini azaltır. İdame kemoterapisi alan hastalarda NK hücre aktivitesindeki artış profilaktik kraniyal radyoterapi ile ilişkili olabilir.
Anahtar Kelimeler
akut lenfoblastik lösemi çocuk interferon doğal öldürücü hücreler
Destekleyen Kurum
İstanbul Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi
Proje Numarası
T-889/02062006
Kaynakça
- 1. Miller JS. The biology of natural killer cells in cancer, infection, and pregnancy. Exp Hematol 2001;29(10):1157-68.
- 2. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000;88(3):577-83.
- 3. Standish LJ, Torkelson C, Hamill FA, Yim D, Hill- Force A, Fitzpatrick A, et al. Immune defects in breast cancer patients after radiotherapy. J Soc Integr Oncol 2008;6(3):110-21.
- 4. Pierson BA, Miller JS. CD56+bright and CD56+dim natural killer cells in patients with chronic myelogenous leukemia progressively decrease in number, respond less to stimuli that recruit clonogenic natural killer cells, and exhibit decreased proliferation on a per cell basis. Blood 1996;88(6):2279-87.
- 5. Zuelzer WW, Inoue S, Thompson RI, Ottenbreit MJ. Long-term cytogenetic studies in acute leukemia of children; the nature of relapse. Am J Hematol 1976;1(2):143-90.
- 6. Yabuhara A, Kawai H. A recycling defect as a characteristic of natural killer cells in childhood acute lymphoblastic leukemia. Pediatr Res 1990;28(6):572-78.
- 7. Van Tilburg CM, van der Velden VHJ, Sanders EAM, Wolfs TFW, Gaiser JF, de Haas V, et al. Reduced versus intensive chemotherapy for childhood acute lymphoblastic leukemia: Impact on lymphocyte compartment composition. Leuk Res 2011;35(4):484-91.
- 8. Perkins JL, Harris A, Pozos TC. Immune Dysfunction After Completion of Childhood Leukemia Therapy. J Pediatr Hematol Oncol 2017;39(1):1-5.
- 9. Wakiguchi H, Kubota H, Hisakawa H, Fujieda M, Kurashige T. Defective natural killer cell activity and deficient production of interferon-γ in children with acute lymphoblastic leukemia. Pediatr Int 1994;36(4):361-5.
- 10. Burchenal JH, Murphy ML. Long-term survivors in acute leukemia. Cancer Res 1965;25(9):1491-4.
- 11. Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALLBFM study group from 1981 to 2000. Leukemia 2010;24(2):265-84.
- 12. Aksu Uzunhan T, Karakas Z, Erdem Kuruca S,Cetin B, Karadenizli S, Akdeniz N, et al. The Impact of Chemotherapy on Natural Killer Cells in Children with Acute Lymphoblastic Leukemia. J Child 2011;11(4):160-9.
- 13. Flohr T, Schrauder A, Cazzaniga G, Panzer- Grümayer R, van der Velden V, Fischer S, et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008;22(4):771-82.
- 14. Lange BJ, Bostrom BC, Cherlow JM, Sensel MG, La MKL, Rackoff W, et al. Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 2002;99(3):825-33.
- 15. Schlager SI, Adams AC. Use of Dyes and Radioisotopic Markers in Cytotoxicity Tests. Methods Enzymol 1983;93:233-45.
- 16. Atasever B, Ertan NZ, Erdem-Kuruca S, Karakas Z. In vitro effects of vitamin C and selenium on NK activity of patients with β-thalassemia major. Pediatr Hematol Oncol 2006;23(3):187-97.
- 17. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65(1-2):55-63.
- 18. Jonges LE, Albertsson P, van Vlierberghe RL, Ensink NG, Johansson BR, van de Velde CJ, et al. The phenotypic heterogeneity of human natural killer cells: presence of at least 48 different subsets in the peripheral blood. Scand J Immunol 2001;53(2):103-10.
- 19. Cook EB, Stahl JL, Lowe L, Chen R, Morgan E, Wilson J, et al. Simultaneous measurement of six cytokines in a single sample of human tears using microparticle-based flow cytometry: Allergics vs. non-allergics. J Immunol Methods 2001;254(1-2):109-18.
- 20. Sørskaar D, Lie SO, Førre O. Natural killer cell activity of peripheral blood and bone marrow mononuclear cells from patients with childhood acute lymphoblastic leukemia. Acta Paediatr Scand 1985;74(3):433-7.
- 21. Jermy A, Lilleyman JS, Jennings R, Rees RC. Spontaneous natural killer cell activity in childhood acute lymphoblastic leukaemia. Eur J Cancer Clin Oncol 1987;23(9):1365-70.
- 22. Aricò M, Lanfranchi A, Molinari E, Maccario R, Nespoli L, Burgio GR. Cell-mediated cytotoxicity in children during and after therapy for acute lymphoblastic leukemia. Pediatr Hematol Oncol 1988;5(4):279-86.
- 23. Abo T, Cooper MD, Balch CM. Postnatal expansion of the natural killer and keller cell population in humans identified by the monoclonal HNK-1 antibody. J Exp Med 1982;155(1):321-6.
- 24. Pinel MI, Esteves EB, Rumjanek VM. Natural killer cell activity in Hodgkin’s disease patients undergoing radiation therapy or chemotherapy and radiation therapy. Clin Lab Haematol 1998;20(5):303-6.
- 25. Kebudi R, Ayan I, Darendeliler E, Agaoglu L, Ekmekçioglu S, Yagci T, et al. Immunologic status in children with brain tumors and the effect of therapy. J Neurooncol 1995;24(3):219-27.
- 26. Yamada S, Kawai H, Miyagawa Y, Komiyama A. Effect of Radiotherapy on Natural Killer Activity in Childhood Acute Lymphoblastic Leukemia and Lymphoma. Leuk Lymphoma 1991;4(5-6):343-9.
- 27. Zarcone D, Tilden AB, Lane VG, Grossi CE. Radiation sensitivity of resting and activated nonspecific cytotoxic cells of T lineage and NK lineage. Blood 1989;73(6):1615-21.
- 28. Mazur B, Olejnik I, Wylezol I, Sonta-Jakimczyk D, Szczepanski T, Karpe J. Assessment of chosen parameters of the immune system in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2003;20(4):303-8.
- 29. Eyrich M, Wiegering V, Lim A, Schrauder A, Winkler B, Schlegel PG. Immune function in children under chemotherapy for standard risk acute lymphoblastic leukaemia - a prospective study of 20 paediatric patients. Br J Haematol 2009;147(3):360-70.
- 30. Ek T, Mellander L, Andersson B, Abrahamsson J. Immune reconstitution after childhood acute lymphoblastic leukemia is most severely affected in the high risk group. Pediatr Blood Cancer 2005;44(5):461-8.
- 31. Kovacs GT, Barany O, Schlick B, Csoka M, Gado J, Ponyi A, et al. Late immune recovery in children treated for malignant diseases. Pathol Oncol Res 2008;14(4):391-7.
Öz
Objective: The aim of this study was to investigate changes in natural killer (NK) cell proportion, NK cell activity, and cytokine levels in children with acute lymphoblastic leukemia (ALL) during and after therapy. Materials and Methods: The study group included 33 ALL patients and the control group consisted of 11 healthy children. The ALL patients were divided into three groups, those who had completed protocol M, receiving maintenance chemotherapy, and whose chemotherapy was discontinued. NK cell cytotoxicity was evaluated at different effector to target (E:T) cell ratios and in lytic units (LU). Expression of CD56, CD3, NKp46, CD2, CD94, NKG2D, and CD16 molecules and levels of the interferon gamma (IFN-γ) and interleukin-15 (IL-15) were measured. Results: NK cell activity at an E:T ratio of 1:1 was higher in patients receiving maintenance chemotherapy compared to the other groups (p<0.05), but there was no difference between the groups in LU (p>0.05). The ratio of CD16+CD56+ cells was smaller in the maintenance chemotherapy group compared to controls (p<0.05). Patients who underwent prophylactic cranial irradiation showed significantly higher NK cytotoxicity at 1:1 E:T ratio compared to those who did not (p<0.05). Eighty-three percent of patients in the maintenance chemotherapy group underwent prophylactic cranial irradiation. The IFN-γ levels were significantly lower in the maintenance chemotherapy and discontinued treatment groups compared to the control group (p<0.05). Conclusion: In children with ALL, chemotherapy reduces the NK cell population and IFN-γ levels. The increase in NK cell activity in patients receiving maintenance chemotherapy may be associated with prophylactic cranial radiotherapy.
Anahtar Kelimeler
Acute lymphoblastic leukemia children interferon natural killer cells
Proje Numarası
T-889/02062006
Kaynakça
- 1. Miller JS. The biology of natural killer cells in cancer, infection, and pregnancy. Exp Hematol 2001;29(10):1157-68.
- 2. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000;88(3):577-83.
- 3. Standish LJ, Torkelson C, Hamill FA, Yim D, Hill- Force A, Fitzpatrick A, et al. Immune defects in breast cancer patients after radiotherapy. J Soc Integr Oncol 2008;6(3):110-21.
- 4. Pierson BA, Miller JS. CD56+bright and CD56+dim natural killer cells in patients with chronic myelogenous leukemia progressively decrease in number, respond less to stimuli that recruit clonogenic natural killer cells, and exhibit decreased proliferation on a per cell basis. Blood 1996;88(6):2279-87.
- 5. Zuelzer WW, Inoue S, Thompson RI, Ottenbreit MJ. Long-term cytogenetic studies in acute leukemia of children; the nature of relapse. Am J Hematol 1976;1(2):143-90.
- 6. Yabuhara A, Kawai H. A recycling defect as a characteristic of natural killer cells in childhood acute lymphoblastic leukemia. Pediatr Res 1990;28(6):572-78.
- 7. Van Tilburg CM, van der Velden VHJ, Sanders EAM, Wolfs TFW, Gaiser JF, de Haas V, et al. Reduced versus intensive chemotherapy for childhood acute lymphoblastic leukemia: Impact on lymphocyte compartment composition. Leuk Res 2011;35(4):484-91.
- 8. Perkins JL, Harris A, Pozos TC. Immune Dysfunction After Completion of Childhood Leukemia Therapy. J Pediatr Hematol Oncol 2017;39(1):1-5.
- 9. Wakiguchi H, Kubota H, Hisakawa H, Fujieda M, Kurashige T. Defective natural killer cell activity and deficient production of interferon-γ in children with acute lymphoblastic leukemia. Pediatr Int 1994;36(4):361-5.
- 10. Burchenal JH, Murphy ML. Long-term survivors in acute leukemia. Cancer Res 1965;25(9):1491-4.
- 11. Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALLBFM study group from 1981 to 2000. Leukemia 2010;24(2):265-84.
- 12. Aksu Uzunhan T, Karakas Z, Erdem Kuruca S,Cetin B, Karadenizli S, Akdeniz N, et al. The Impact of Chemotherapy on Natural Killer Cells in Children with Acute Lymphoblastic Leukemia. J Child 2011;11(4):160-9.
- 13. Flohr T, Schrauder A, Cazzaniga G, Panzer- Grümayer R, van der Velden V, Fischer S, et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008;22(4):771-82.
- 14. Lange BJ, Bostrom BC, Cherlow JM, Sensel MG, La MKL, Rackoff W, et al. Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 2002;99(3):825-33.
- 15. Schlager SI, Adams AC. Use of Dyes and Radioisotopic Markers in Cytotoxicity Tests. Methods Enzymol 1983;93:233-45.
- 16. Atasever B, Ertan NZ, Erdem-Kuruca S, Karakas Z. In vitro effects of vitamin C and selenium on NK activity of patients with β-thalassemia major. Pediatr Hematol Oncol 2006;23(3):187-97.
- 17. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65(1-2):55-63.
- 18. Jonges LE, Albertsson P, van Vlierberghe RL, Ensink NG, Johansson BR, van de Velde CJ, et al. The phenotypic heterogeneity of human natural killer cells: presence of at least 48 different subsets in the peripheral blood. Scand J Immunol 2001;53(2):103-10.
- 19. Cook EB, Stahl JL, Lowe L, Chen R, Morgan E, Wilson J, et al. Simultaneous measurement of six cytokines in a single sample of human tears using microparticle-based flow cytometry: Allergics vs. non-allergics. J Immunol Methods 2001;254(1-2):109-18.
- 20. Sørskaar D, Lie SO, Førre O. Natural killer cell activity of peripheral blood and bone marrow mononuclear cells from patients with childhood acute lymphoblastic leukemia. Acta Paediatr Scand 1985;74(3):433-7.
- 21. Jermy A, Lilleyman JS, Jennings R, Rees RC. Spontaneous natural killer cell activity in childhood acute lymphoblastic leukaemia. Eur J Cancer Clin Oncol 1987;23(9):1365-70.
- 22. Aricò M, Lanfranchi A, Molinari E, Maccario R, Nespoli L, Burgio GR. Cell-mediated cytotoxicity in children during and after therapy for acute lymphoblastic leukemia. Pediatr Hematol Oncol 1988;5(4):279-86.
- 23. Abo T, Cooper MD, Balch CM. Postnatal expansion of the natural killer and keller cell population in humans identified by the monoclonal HNK-1 antibody. J Exp Med 1982;155(1):321-6.
- 24. Pinel MI, Esteves EB, Rumjanek VM. Natural killer cell activity in Hodgkin’s disease patients undergoing radiation therapy or chemotherapy and radiation therapy. Clin Lab Haematol 1998;20(5):303-6.
- 25. Kebudi R, Ayan I, Darendeliler E, Agaoglu L, Ekmekçioglu S, Yagci T, et al. Immunologic status in children with brain tumors and the effect of therapy. J Neurooncol 1995;24(3):219-27.
- 26. Yamada S, Kawai H, Miyagawa Y, Komiyama A. Effect of Radiotherapy on Natural Killer Activity in Childhood Acute Lymphoblastic Leukemia and Lymphoma. Leuk Lymphoma 1991;4(5-6):343-9.
- 27. Zarcone D, Tilden AB, Lane VG, Grossi CE. Radiation sensitivity of resting and activated nonspecific cytotoxic cells of T lineage and NK lineage. Blood 1989;73(6):1615-21.
- 28. Mazur B, Olejnik I, Wylezol I, Sonta-Jakimczyk D, Szczepanski T, Karpe J. Assessment of chosen parameters of the immune system in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2003;20(4):303-8.
- 29. Eyrich M, Wiegering V, Lim A, Schrauder A, Winkler B, Schlegel PG. Immune function in children under chemotherapy for standard risk acute lymphoblastic leukaemia - a prospective study of 20 paediatric patients. Br J Haematol 2009;147(3):360-70.
- 30. Ek T, Mellander L, Andersson B, Abrahamsson J. Immune reconstitution after childhood acute lymphoblastic leukemia is most severely affected in the high risk group. Pediatr Blood Cancer 2005;44(5):461-8.
- 31. Kovacs GT, Barany O, Schlick B, Csoka M, Gado J, Ponyi A, et al. Late immune recovery in children treated for malignant diseases. Pathol Oncol Res 2008;14(4):391-7.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Proje Numarası | T-889/02062006 |
| Yayımlanma Tarihi | 10 Şubat 2021 |
| Gönderilme Tarihi | 21 Aralık 2020 |
| Yayımlandığı Sayı | Yıl 2021 Cilt: 4 Sayı: 1 |
