Research Article
Year 2024,
Volume: 31 Issue: 2, 151 - 157, 29.06.2024
Abstract
Objective: After kidney transplantation, CD8+ T cells can infiltrate the kidney and cause necrosis, tubulitis, and even transplant rejection. For this reason, control of the T cell response is very important, and T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed death 1 (PD-1) molecules play a role in regulating the T cell response. It is thought that the levels of TIM-3 and PD-1 expressions may be guiding in determining the clinical course after transplantation. This study aimed to determine the relationship between the mRNA levels of PD-1 and TIM-3 genes in peripheral blood samples taken from kidney transplant patients and the clinical conditions of the patients.
Material and Method: 60 peripheral blood samples were collected from 30 kidney transplant patients, both pre-transplantation (pre-tx) and post-transplantation (post-tx). CD8+ T cells were separated from other lymphocytes by magnetic cell separation system (MACS) and their purity was determined by flow cytometry. Then, RNA was isolated and after cDNA conversion, the expressions of PD-1 and TIM-3 genes were determined by real-time polymerase chain reaction.
Results: While it was determined that the TIM-3 gene expression level increased in patients with acute tubular necrosis, antibody-mediated rejection and cell-mediated rejection findings (p<0.001), no correlation was found between PD-1 expression levels and the clinical findings of the patients.
Conclusion: It is thought that comparing TIM-3 mRNA levels before and after kidney transplantation may be a useful tool in evaluating the clinical status of patients.
Ethical Statement
Ethical approval for this study was obtained from Health Science University Tepecik Training and Research Hospital Noninvasive Ethics Committee with the number 2022/05-31.
Supporting Institution
Izmir Katip Celebi University Scientific Research Project Coordinator
Project Number
2019-TDR-SABE-0006
References
- 1. Luo Y, Shi B, Qian Y, Bai H, Chang J. Sequential Monitoring of TIM-3 Gene Expression in Peripheral Blood for Diagnostic and Prognostic Evaluation of Acute Rejection in Renal Graft Recipients. Transp Proceed 2021;43(10):3669-3674.
- 2. Grywalska E, Smarz-Widelska I, Mertowski S, Gosik K, Mielnik M, Podgajna M et al. CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides. Archivum Immunologiae et Therapiae Experimentalis 2019;67(5):335-349.
- 3. Ingulli E. Mechanism of Cellular Rejection in Transplantation. Ped Nephr 2010;25(1):61-74.
- 4. Robertson H, Wheeler J, Kirby JA, Morley AR. Renal Allograft Rejectıon-In Sıtu Demonstration of Cytotoxıc Intratubular Cells. Transplantation 1996;61(10):1546-1549.
- 5. Koyama I, Nadazdin O, Boskovic S, Ochiai T, Smith RN, Sykes M. Depletion of CD8 Memory T Cells for Induction of Tolerance of a Previously Transplanted Kidney Allograft. Am J of Transp 2007;7(5):1055-1061.
- 6. Betjes MG, Meijers RW, de Wit EA, Weimar W, Litjens NH. Terminally Differentiated CD8+ Temra Cells are Associated with the Risk for Acute Kidney Allograft Rejection. Transplantation 2012;94(1):63-69.
- 7. Yap M, Brouard S, Pecqueur C, Degauque N. Targeting CD8 T-Cell Metabolism in Transplantation. Front in Immunol 2015;6:547.
- 8. Hunter MC, Teijeira A, Halin C. T Cell Trafficking Through Lymphatic Vessels. Front in Immunol 2016;7:613.
- 9. Kumar BV, Connors TJ, Farber DL. Human T Cell Development, Localization, and Function Throughout Life. Immunity 2018;48(2):202-213.
- 10. Agarwal A, Newell KA. The Role of Positive Costimulatory Molecules in Transplantation and Tolerance. Current Opinion in Organ Transplantation 2008;13(4):366-372.
- 11. Bour‐Jordan H, Esensten JH, Martinez‐Llordella M, Penaranda C, Stumpf M et al. Intrinsic and Extrinsic Control of Peripheral T‐Cell Tolerance by Costimulatory Molecules of the CD28/B7 Family. Immunol Rev 2011;241(1):180-205.
- 12. Esensten J, Helou, YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: From Mechanism to Therapy. Immunity 2016;44(5):973-988.
- 13. Qin W, Hu L, Zhang X, Jiang S, Li J, Zhang Z et al. The Diverse Function of PD-1/PD-L Pathway Beyond Cancer. Front in Immunol 2019;10:2298.
- 14. Yoneda A, Jinushi M. T Cell Immunoglobulin Domain and Mucin Domain-3 as an Emerging Target for Immunotherapy in Cancer Management. ImmunoTargets and Therapy 2013;2:135.
- 15. Qin S, Dong B, Yi M, Chu Q, Wu K. Prognostic Values of TIM-3 Expression in Patients with Solid Tumors: a Meta-Analysis and Database Evaluation. Front in Oncol 2020;10:1288.
- 16. Wang H, Zhang X, Zheng X, Lan Z, Shi J, Jiang J et al. Prevention of Allograft Rejection in Heart Transplantation Through Concurrent Gene Silencing of TLR and Kinase Signaling Pathways. Scien Reports 2016;6(1):1-14.
- 17. Karahan HI, Soyöz M, Pehlivan M, Tatar E, Uslu , Gürbüz, BÇ et al. Assessment of Interleukin 2 Cytokine Expression Levels After Renal Transplantation. Transp Proceed 2019;51(4):1074-1077.
- 18. Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L et al. Expression of Human TIM‐1 and TIM‐3 on Lymphocytes from Systemic Lupus Erythematosus Patients. Scand J of Immunol 2008;67(1):63-70.
- 19. Han FL, Liang F, Jiang TC, Liu M. Increased Expression of CXCR5 and CXCL13 in Mice with Experimental Autoimmune Myocarditis. Eur Rev Med Pharmacol Sci 2017;21(8):1860-7.
- 20. Williams WW, Taheri D, Tolkoff-Rubin N, Colvin RB. Clinical Role of the Renal Transplant Biopsy. Nat Rev Neph 2012;8(2):110-121.
- 21. Poggio ED, McClelland RL, Blank KN, Hansen S, Bansal S, Bomback AS et al. Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications. Clin J of the Am Soc of Neph 2020;15(11):1595-1602.
- 22. Giarraputo A, Barison I, Fedrigo M, Burrello J, Castellani C, Tona F et al. A Changing Paradigm in Heart Transplantation: An Integrative Approach for Invasive and Non-Invasive Allograft Rejection Monitoring. Biomol 2021;11(2):201.
- 23. Cuervo Florez M, Bruner J, Zarrinpar A. Progress and Challenges in Diagnosis and Treatment of Rejection Following Liver Transplantation. Curr Op in Organ Transp 2021;26(6):669-674.
- 24. Friedewald JJ, Kurian SM, Heilman RL, Whisenant TC, Poggio ED et al. Development and Clinical Validity of a Novel Blood‐Based Molecular Biomarker for Subclinical Acute Rejection Following Kidney Transplant. Am J of Transp 2019;19(1):98-109.
- 25. Tu L, Guan R, Yang H, Zhou Y, Hong W, Ma L et al. Assessment of the Expression of the immune Checkpoint Molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 Across Different Cancers in Relation to Treatment Response, Tumor‐Infiltrating Immune Cells and Survival. Int J of Canc 2020;147(2):423-439.
- 26. Shahbaz SK, Barabadi M, Ahmadpour P, Pourrezagholi F, Nafar M et al. Sequential Monitoring of TIM-3 mRNA Expression in Blood and Urine Samples of Renal Transplant Recipients. Transp Immunol 2019;54:9-16. 27. Das M, Zhu C, Kuchroo VK. Tim‐3 and its Role in Regulating Anti‐Tumor Immunity. Immunol Rev 2017;276(1):97-111.
- 28. Banerjee H, Nieves-Rosado H, Kulkarni A, Murter B, McGrath KV et al. Expression of Tim-3 Drives Phenotypic and Functional Changes in Treg Cells in Secondary Lymphoid Organs and the Tumor Microenvironment. Cell Reports 2021;36(11):109699.
- 29. Renesto PG, Ponciano VC, Cenedeze MA, Camara NS, Pacheco‐Silva A. High Expression of Tim‐3 mRNA in Urinary Cells from Kidney Transplant Recipients with Acute Rejection. Am J of Transp 2007;7(6):1661-1665.
- 30. Luo Y, Shi B, Qia Y, Bai H, Chang J. Sequential Monitoring of TIM-3 Gene Expression in Peripheral Blood for Diagnostic and Prognostic Evaluation of Acute Rejection in Renal Graft Recipients. In Transp Proc 2011;43(10):3669-3674.
- 31. Ponciano VC, Renesto PG, Nogueira E, Rangel ÉB, Cenedeze M et al. Tim-3 Expression in Human Kidney Allografts. Transp Immunol 2007;17(3):215-222.
- 32. Manfro RC, Aquino-Dias EC, Joelsons G, Nogare AL, Carpio VN et al. Noninvasive Tim-3 Messenger RNA Evaluation in Renal Transplant Recipients with Graft Dysfunction. Transplantation 2008;86(12):1869-1874.
- 33. Varki V, Ioffe OB, Bentzen SM, Heath J, Cellini A, Feliciano J, Zandberg DP. PD-L1, B7-H3, and PD-1 Expression in Immunocompetent vs. Immunosuppressed Patients with Cutaneous Squamous Cell Carcinoma. Canc Immunol, Immunother 2018;67(5):805-814.
- 34. Kinch A, Sundström C, Baecklund E, Backlin C, Molin D, et al. Expression of PD-1, PD-L1, and PD-L2 in Posttransplant Lymphoproliferative Disorder After Solid Organ Transplantation. Leukemia & Lymphoma 2019;60(2):376-384.
- 35. Bishawi M, Bowles D, Pla MM, Oakes F, Chiang Y et al. PD-1 and PD-L1 Expression in Cardiac Transplantation. Cardiovas Pathol 2021;54:107331.
- 36. Pike R, Thomas N, Workman S, Ambrose L, Guzman D et al. PD1-expressing T Cell Subsets Modify the Rejection Risk in Renal Transplant Patients. Front in Immunol 2016;7:126.
- 37. Takahashi T, Hsiao HM, Tanaka S, Li W, Higashikubo R et al. PD‐1 Expression on CD 8+ T Cells Regulates Their Differentiation within Lung Allografts and is Critical for Tolerance Induction. Am J of Transp 2018;18(1):216-225.
Year 2024,
Volume: 31 Issue: 2, 151 - 157, 29.06.2024
Abstract
Amaç: T hücresi immünoglobulin ve müsin domain 3 (TIM-3) ve programlanmış ölüm 1 (PD-1), T hücre yanıtının düzenlenmesinde önemli roller oynar. Böbrek naklinden sonra CD8+ T hücreleri böbreğe sızarak nekroz, tübülit ve hatta nakil reddine neden olabilir. Sonuç olarak böbrek nakli alıcılarından alınan periferik kan örneklerinde PD-1 ve TIM-3 genlerinin mRNA düzeylerini inceliyoruz.
Gereç ve Yöntem: 29 hastadan hem transplantasyon öncesi (tx öncesi) hem de transplantasyon sonrası (tx sonrası) 58 periferik kan örneği toplandı. CD8+ T hücrelerini ayırmak için hemen MACS hücre ayırma sistemi kullanıldı. Toplanan hücrelerin saflığı flow sitometri ile belirlendi. RNA izolasyonu ve cDNA dönüşümünden sonra PD-1 ve TIM-3 genlerinin ifadelerini ölçmek için gerçek zamanlı polimeraz zincir reaksiyonu gerçekleştirildi.
Bulgular: Hastaların %31, %45 ve %7'sinde PD-1 seviyelerinde artış, azalma ve değişiklik görülmezken, %76'sında Tim-3 seviyelerinde azalma, %21'inde ise artış görüldü. Ayrıca TIM-3 gen ekspresyon düzeylerinin rejeksiyon ataklarıyla pozitif yönde ilişkili olduğu belirlendi (p<0,001).
Sonuç: Böbrek nakli öncesi ve sonrası TIM-3 mRNA düzeylerinin karşılaştırılması, hastaların klinik durumunun değerlendirilmesinde yararlı bir araç olabilir.
Project Number
2019-TDR-SABE-0006
References
- 1. Luo Y, Shi B, Qian Y, Bai H, Chang J. Sequential Monitoring of TIM-3 Gene Expression in Peripheral Blood for Diagnostic and Prognostic Evaluation of Acute Rejection in Renal Graft Recipients. Transp Proceed 2021;43(10):3669-3674.
- 2. Grywalska E, Smarz-Widelska I, Mertowski S, Gosik K, Mielnik M, Podgajna M et al. CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides. Archivum Immunologiae et Therapiae Experimentalis 2019;67(5):335-349.
- 3. Ingulli E. Mechanism of Cellular Rejection in Transplantation. Ped Nephr 2010;25(1):61-74.
- 4. Robertson H, Wheeler J, Kirby JA, Morley AR. Renal Allograft Rejectıon-In Sıtu Demonstration of Cytotoxıc Intratubular Cells. Transplantation 1996;61(10):1546-1549.
- 5. Koyama I, Nadazdin O, Boskovic S, Ochiai T, Smith RN, Sykes M. Depletion of CD8 Memory T Cells for Induction of Tolerance of a Previously Transplanted Kidney Allograft. Am J of Transp 2007;7(5):1055-1061.
- 6. Betjes MG, Meijers RW, de Wit EA, Weimar W, Litjens NH. Terminally Differentiated CD8+ Temra Cells are Associated with the Risk for Acute Kidney Allograft Rejection. Transplantation 2012;94(1):63-69.
- 7. Yap M, Brouard S, Pecqueur C, Degauque N. Targeting CD8 T-Cell Metabolism in Transplantation. Front in Immunol 2015;6:547.
- 8. Hunter MC, Teijeira A, Halin C. T Cell Trafficking Through Lymphatic Vessels. Front in Immunol 2016;7:613.
- 9. Kumar BV, Connors TJ, Farber DL. Human T Cell Development, Localization, and Function Throughout Life. Immunity 2018;48(2):202-213.
- 10. Agarwal A, Newell KA. The Role of Positive Costimulatory Molecules in Transplantation and Tolerance. Current Opinion in Organ Transplantation 2008;13(4):366-372.
- 11. Bour‐Jordan H, Esensten JH, Martinez‐Llordella M, Penaranda C, Stumpf M et al. Intrinsic and Extrinsic Control of Peripheral T‐Cell Tolerance by Costimulatory Molecules of the CD28/B7 Family. Immunol Rev 2011;241(1):180-205.
- 12. Esensten J, Helou, YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: From Mechanism to Therapy. Immunity 2016;44(5):973-988.
- 13. Qin W, Hu L, Zhang X, Jiang S, Li J, Zhang Z et al. The Diverse Function of PD-1/PD-L Pathway Beyond Cancer. Front in Immunol 2019;10:2298.
- 14. Yoneda A, Jinushi M. T Cell Immunoglobulin Domain and Mucin Domain-3 as an Emerging Target for Immunotherapy in Cancer Management. ImmunoTargets and Therapy 2013;2:135.
- 15. Qin S, Dong B, Yi M, Chu Q, Wu K. Prognostic Values of TIM-3 Expression in Patients with Solid Tumors: a Meta-Analysis and Database Evaluation. Front in Oncol 2020;10:1288.
- 16. Wang H, Zhang X, Zheng X, Lan Z, Shi J, Jiang J et al. Prevention of Allograft Rejection in Heart Transplantation Through Concurrent Gene Silencing of TLR and Kinase Signaling Pathways. Scien Reports 2016;6(1):1-14.
- 17. Karahan HI, Soyöz M, Pehlivan M, Tatar E, Uslu , Gürbüz, BÇ et al. Assessment of Interleukin 2 Cytokine Expression Levels After Renal Transplantation. Transp Proceed 2019;51(4):1074-1077.
- 18. Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L et al. Expression of Human TIM‐1 and TIM‐3 on Lymphocytes from Systemic Lupus Erythematosus Patients. Scand J of Immunol 2008;67(1):63-70.
- 19. Han FL, Liang F, Jiang TC, Liu M. Increased Expression of CXCR5 and CXCL13 in Mice with Experimental Autoimmune Myocarditis. Eur Rev Med Pharmacol Sci 2017;21(8):1860-7.
- 20. Williams WW, Taheri D, Tolkoff-Rubin N, Colvin RB. Clinical Role of the Renal Transplant Biopsy. Nat Rev Neph 2012;8(2):110-121.
- 21. Poggio ED, McClelland RL, Blank KN, Hansen S, Bansal S, Bomback AS et al. Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications. Clin J of the Am Soc of Neph 2020;15(11):1595-1602.
- 22. Giarraputo A, Barison I, Fedrigo M, Burrello J, Castellani C, Tona F et al. A Changing Paradigm in Heart Transplantation: An Integrative Approach for Invasive and Non-Invasive Allograft Rejection Monitoring. Biomol 2021;11(2):201.
- 23. Cuervo Florez M, Bruner J, Zarrinpar A. Progress and Challenges in Diagnosis and Treatment of Rejection Following Liver Transplantation. Curr Op in Organ Transp 2021;26(6):669-674.
- 24. Friedewald JJ, Kurian SM, Heilman RL, Whisenant TC, Poggio ED et al. Development and Clinical Validity of a Novel Blood‐Based Molecular Biomarker for Subclinical Acute Rejection Following Kidney Transplant. Am J of Transp 2019;19(1):98-109.
- 25. Tu L, Guan R, Yang H, Zhou Y, Hong W, Ma L et al. Assessment of the Expression of the immune Checkpoint Molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 Across Different Cancers in Relation to Treatment Response, Tumor‐Infiltrating Immune Cells and Survival. Int J of Canc 2020;147(2):423-439.
- 26. Shahbaz SK, Barabadi M, Ahmadpour P, Pourrezagholi F, Nafar M et al. Sequential Monitoring of TIM-3 mRNA Expression in Blood and Urine Samples of Renal Transplant Recipients. Transp Immunol 2019;54:9-16. 27. Das M, Zhu C, Kuchroo VK. Tim‐3 and its Role in Regulating Anti‐Tumor Immunity. Immunol Rev 2017;276(1):97-111.
- 28. Banerjee H, Nieves-Rosado H, Kulkarni A, Murter B, McGrath KV et al. Expression of Tim-3 Drives Phenotypic and Functional Changes in Treg Cells in Secondary Lymphoid Organs and the Tumor Microenvironment. Cell Reports 2021;36(11):109699.
- 29. Renesto PG, Ponciano VC, Cenedeze MA, Camara NS, Pacheco‐Silva A. High Expression of Tim‐3 mRNA in Urinary Cells from Kidney Transplant Recipients with Acute Rejection. Am J of Transp 2007;7(6):1661-1665.
- 30. Luo Y, Shi B, Qia Y, Bai H, Chang J. Sequential Monitoring of TIM-3 Gene Expression in Peripheral Blood for Diagnostic and Prognostic Evaluation of Acute Rejection in Renal Graft Recipients. In Transp Proc 2011;43(10):3669-3674.
- 31. Ponciano VC, Renesto PG, Nogueira E, Rangel ÉB, Cenedeze M et al. Tim-3 Expression in Human Kidney Allografts. Transp Immunol 2007;17(3):215-222.
- 32. Manfro RC, Aquino-Dias EC, Joelsons G, Nogare AL, Carpio VN et al. Noninvasive Tim-3 Messenger RNA Evaluation in Renal Transplant Recipients with Graft Dysfunction. Transplantation 2008;86(12):1869-1874.
- 33. Varki V, Ioffe OB, Bentzen SM, Heath J, Cellini A, Feliciano J, Zandberg DP. PD-L1, B7-H3, and PD-1 Expression in Immunocompetent vs. Immunosuppressed Patients with Cutaneous Squamous Cell Carcinoma. Canc Immunol, Immunother 2018;67(5):805-814.
- 34. Kinch A, Sundström C, Baecklund E, Backlin C, Molin D, et al. Expression of PD-1, PD-L1, and PD-L2 in Posttransplant Lymphoproliferative Disorder After Solid Organ Transplantation. Leukemia & Lymphoma 2019;60(2):376-384.
- 35. Bishawi M, Bowles D, Pla MM, Oakes F, Chiang Y et al. PD-1 and PD-L1 Expression in Cardiac Transplantation. Cardiovas Pathol 2021;54:107331.
- 36. Pike R, Thomas N, Workman S, Ambrose L, Guzman D et al. PD1-expressing T Cell Subsets Modify the Rejection Risk in Renal Transplant Patients. Front in Immunol 2016;7:126.
- 37. Takahashi T, Hsiao HM, Tanaka S, Li W, Higashikubo R et al. PD‐1 Expression on CD 8+ T Cells Regulates Their Differentiation within Lung Allografts and is Critical for Tolerance Induction. Am J of Transp 2018;18(1):216-225.
There are 36 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Gene Expression, Transplantation Immunology |
| Journal Section | Research Articles |
| Authors | |
| Project Number | 2019-TDR-SABE-0006 |
| Publication Date | June 29, 2024 |
| Submission Date | November 15, 2023 |
| Acceptance Date | May 10, 2024 |
| Published in Issue | Year 2024 Volume: 31 Issue: 2 |
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