Backgrounds: Recent advances in post Kidney Transplantation (KT) care, have led to a dramatic improvement in short-term outcomes in order to achieve transplantation tolerance; including the ideal tool for clinical monitoring & new therapeutic line. This study was undertaken to analyze the CD62L in Kidney Transplant Recipients (KTRs) and to investigate its efficacy as a marker of good graft survival. Methods: Fifty pediatric KTRs and 12 healthy controls were included in the study, the frequency of T cell activation markers; CD62L was measured with flow cytometry after renal transplantation. Clinical, laboratory, immunosuppressive therapy data and graft function of transplant recipients were collected and correlated with their CD62L peripheral blood percentage. Results: The circulating CD62L% was significantly more in transplant recipients than controls (44.74% ± 17.45% vs. 33.36% ± 11.54%, p = 0.02). CD 62L% was more frequent in recipients of living related donors (p = 0.05), positively correlated with donor age (p = 0.04, r = -0.29 * ) and CD 4% (p = 0.000, r = 0.615). CD26L% did not show significant association with acute rejection or chronic rejection (p = 0.432, p = 0.91 respectively) or with graft function (serum creatinine or eGFR, p = 0.086, p = 0.988 respectively) or immunosuppressive medications. Conclusion: Peripheral CD62L% is increased after KT than healthy controls, however, it cannot reflect either clinical (serum creatinine and eGFR) or pathological renal graft injury. CD62L surface marker needs more analysis for its potential diagnostic and therapeutic implications as a Treg cell activation marker.
KeywordsCD62LRegulatory T CellsTransplantationGraft SurvivalChildren
Krajewska, M., Koscielska-Kasprzak, K., Kaminska, D., Zabinska, M., Myszka-Kozlowska, M., Gomulkiewicz, A., Dziegiel, P. and Klinger, M. (2019) Kidney Transplant Outcome Is Associated with Regulatory T Cell Population and Gene Expression Early after Transplantation. Journal of Immunology Research, 2019, Article ID: 7452019. https://doi.org/10.1155/2019/7452019
Bestard, O., Cruzado, J.M., Mestre, M., Caldés, A., et al. (2007) Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates. The Journal of Immunology, 179, 4901-4909. https://doi.org/10.4049/jimmunol.179.7.4901
Fadel, F.I., Elghoroury, E.A., Elshamaa, M.F., Bazaraa, H.M., Salah, D.M., Kassem, N.M.A., Ibrahim, M.H., El-Saaid, G.S., Nasr, S.A. and Koura, H.M. (2015) Lymphocyte Activation Markers in Pediatric Kidney Transplant Recipients. International Journal of Biomedical Science, 11, 121-130.
Hu, M., Wang, Y.M., Wang, Y., Zhang, G.Z., Zheng, G., Shounan, Y., O’Connell, P.J.O., Harris, D.C.H. and Alexander, S.I. (2016) Regulatory T Cells in Kidney Disease and Transplantation. Kidney International, 90, 502-514. https://doi.org/10.1016/j.kint.2016.03.022
Zwang, N.A. and Leventhal, J.R. (2017) Cell Therapy in Kidney Transplantation: Focus on Regulatory T Cells. Journal of the American Society of Nephrology, 28, 1960-1972. https://doi.org/10.1681/ASN.2016111206
Ivetic, A., Green, H.L.G. and Hart, S.J. (2019) L-Selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling. Frontiers in Immunology, 10, 1068. https://doi.org/10.3389/fimmu.2019.01068
Zarbock, A., Ley, K., McEver, R.P. and Hidalgo, A. (2011) Leukocyte Ligands for Endothelial Selectins: Specialized Glycoconjugates That Mediate Rolling and Signaling under Flow. Blood, 118, 6743-6751. https://doi.org/10.1182/blood-2011-07-343566
Townamchai, N., Safa, K. and Chandraker, A. (2013) Immunologic Monitoring in Kidney Transplant Recipients. Kidney Research and Clinical Practice, 32, 52-61. https://doi.org/10.1016/j.krcp.2013.04.002
Atif, M., Conti, F., Gorochov, G., Oo, Y.H. and Miyara, M. (2020) Regulatory T Cells in Solid Organ Transplantation. Clinical & Translational Immunology, 9, e01099. https://doi.org/10.1002/cti2.1099
Kanamori, M., Nakatsukasa, H., Okada, M., et al. (2016) Induced Regulatory T Cells: Their Development, Stability, and Applications. Trends in Immunology, 37, 803-811. https://doi.org/10.1016/j.it.2016.08.012
Yang, S.L., Wang, D., Wu, W.Z., Lin, W.H., Xu, T.Z., Cai, J.Q. and Tan, J.M. (2008) Comparison of Single Bolus ATG and Basiliximab as Induction Therapy in Presensitized Renal Allograft Recipients Receiving Tacrolimus-Based Immunosuppressive Regimen. Transplant Immunology, 18, 281-285. https://doi.org/10.1016/j.trim.2007.08.002
Steiner, R.W. and Awdishu, L. (2011) Steroids in Kidney Transplant Patients. Seminars in Immunopathology, 33, 157-167. https://doi.org/10.1007/s00281-011-0259-7
Chelala, D.N., Mourani, C., Moukarzel, M. and Azar, H. (2015) Immunosuppressive Protocols in Kidney Transplantation: With or without Induction? Journal Medical Libanais, 63, 150-153. https://doi.org/10.12816/0015838
Huang, P.C., Yang, C.Y., Lee, C.Y., Yeh, C.C., et al. (2013) Pediatric Renal Transplantation: Results and Prognostic Factors. Asian Journal of Surgery, 36, 53-57. https://doi.org/10.1016/j.asjsur.2012.09.001
Fleiner, F., Fritsche, L., Glander, P., Neumayer, H.H. and Budde, K. (2006) Reporting of Rejection after Renal Transplantation in Large Immunosuppressive Trials: Biopsy-Proven, Clinical, Presumed, or Treated Rejection? Transplantation, 81, 655-659. https://doi.org/10.1097/01.tp.0000214933.73927.4e
Chapman, J.R., O’Connell, P.J. and Nankivell, B.J. (2005) Chronic Renal Allograft Dysfunction. Journal of the American Society of Nephrology, 16, 3015-3026. https://doi.org/10.1681/ASN.2005050463
Suresh, K.P. and Chandrashekara, S. (2012) Sample Size Estimation and Power Analysis for Clinical Research Studies. Journal of Human Reproductive Sciences, 5, 7-13. https://doi.org/10.4103/0974-1208.97779
Bar-Ephraim, Y.E., Koning, J.J., Ruiz, E.B., Konijn, T., Mourits, V.P., Lakeman, K.M., et al. (2019) CD62L Is a Functional and Phenotypic Marker for Circulating Innate Lymphoid Cell Precursors. Journal of Immunology, 202, 171-182. https://doi.org/10.4049/jimmunol.1701153
Bjorklund, A.K., Forkel, M., Picelli, S., Konya, V., Theorell, V., Friberg, D., Sandberg, R. and Mjosberg, J. (2016) The Heterogeneity of Human CD127+ Innate Lymphoid Cells Revealed by Single-Cell RNA Sequencing. Nature Immunology, 17, 451-460. https://doi.org/10.1038/ni.3368
Illanova, F., Flutter, B., Tosi, I., Grys, K., Sreeneebus, H., Perera, G.K., Chapman, A., Smith, C.H., Meglio, P.D. and Nestle, F.O. (2014) Characterization of Innate Lymphoid Cells in Human Skin and Blood Demonstrates Increase of NKp44+ ILC3 in Psoriasis. Journal of Investigative Dermatology, 134, 984-991. https://doi.org/10.1038/jid.2013.477
Teunissen, M.B.M., Munneke, J.M., Bernink, J.H., Spuls, P.I., Res, P.C.M., Velde, A.T., Cheuk, S., Brouwer, M.W.D., Menting, S.P., Eidsmo, L., et al. (2014) Composition of Innate Lymphoid Cell Subsets in the Human Skin: Enrichment of NCR+ ILC3 in Lesional Skin and Blood of Psoriasis Patients. Journal of Investigative Dermatology, 134, 2351-2360. https://doi.org/10.1038/jid.2014.146
Bernink, J.H., Peters, C.P., Munneke, M., te Velde, A.A., Meijer, S.L., Weijer, K., Hreggvidsdottir, H.S., Heinsbroek, S.E., Legrand, N., Buskens, C.J., et al. (2013) Human Type 1 Innate Lymphoid Cells Accumulate in Inflamed Mucosal Tissues. Nature Immunology, 14, 221-229. https://doi.org/10.1038/ni.2534
Tang, M.L.K., Steeber, D.A., Zhang, X.-Q. and Tedder, T.F. (1998) Intrinsic Differences in L-Selectin Expression Levels Affect T and B Lymphocyte Subset-Specific Recirculation Pathways. Journal of Immunology, 160, 5113-5121.
Yang, S., Liu, F., Wang, J.W., Rosenberg, S.A. and Morgan, R.A. (2011) The Shedding of CD62L (L-Selectin) Regulates the Acquisition of Lytic Activity in Human Tumor Reactive T Lymphocytes. PLoS ONE, 6, e22560. https://doi.org/10.1371/journal.pone.0022560
Mason, G.M., Lowe, K., Melchiotti, R., et al. (2015) Phenotypic Complexity of the Human Regulatory T Cell Compartment Revealed by Mass Cytometry. Journal of Immunology, 195, 2030-2037. https://doi.org/10.4049/jimmunol.1500703
Chesnaye, N.C., van Stralen, J.K., Bonthuis, M., Groothoff, J.W., Harambat, J., Schaefer, F., Canpolat, N., Garnier, A., Heaf, J. and de Jong, H. (2017) Recipients in a European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplantation Association Registry Study. Nephrology Dialysis Transplantation, 32, 1949-1956. https://doi.org/10.1093/ndt/gfx261
Chavalitdhamrong, D., Gill, J., Takemoto, S., Madhira, B.R., Cho, Y.W., Shah, T. and Bunnapradist, S. (2008) Patient and Graft Outcomes from Deceased Kidney Donors Age 70 Years and Older: An Analysis of the Organ Procurement Transplant Network/United Network of Organ Sharing Database. Transplantation, 85, 1573-1579. https://doi.org/10.1097/TP.0b013e31817059a1
Waiser, J., Schreiber, M., Budde, K., Fritsche, L., Bohler, T., Hauser, I. and Neumayer, H.H. (2000) Age-Matching in Renal Transplantation. Nephrology Dialysis Transplantation, 15, 696-700. https://doi.org/10.1093/ndt/15.5.696
Lee, S.H., Oh, C.K., Shin, G.T., Kim, H., Kim, S.J. and Kim, S.I. (2014) Age Matching Improves Graft Survival after Living Donor Kidney Transplantation. Transplantation Proceedings, 46, 449-453. https://doi.org/10.1016/j.transproceed.2013.10.049
Chiu, B.C., Stolberg, V.R. and Chensu, S.W. (2007) Age-Related Loss of CD62L Impairs Lymph Node CD4 T Cell Mobilization. Open Longevity Science, 1, 1-7. https://doi.org/10.2174/1874369200701010001
Merino, D., Segundo, D.S., Medina, J.M., Rodrigo, E., Asensio, E., Irure, J., Fernández-Fresnedo, G., Arias, M.A. and López-Hoyos, M. (2016) Different in Vitro Proliferation and Cytokine-Production Inhibition of Memory T Cell Subsets after Calcineurin and mTOR Inhibitors Treatment. Immunology, 148, 206-215. https://doi.org/10.1111/imm.12603
Nasimudeen, R., Francis, S., Sreelatha, M. and Puthenparambath, S. (2019) Comparison of Tacrolimus and Sirolimus Based Regimens on Regulatory T Cell Levels in Renal Transplant Recipients: A Study from a Tertiary Care Centre in Kerala, India. India Journal of Clinical and Diagnostic Research, 13, EC01-EC03. https://doi.org/10.7860/JCDR/2019/42355.13190
Han, J.W., Joo, D.J., Kim, J.H., Rha, M.-S., Koh, J.Y., Park, H.J., Lee, J.G., Kim, M.S., Kim, S., Shin, E.C., Park, J.Y. and Park, S.H. (2020) Early Reduction of Regulatory T Cells Is Associated with Acute Rejection in Liver Transplantation under Tacrolimus-Based Immunosuppression with Basiliximab Induction. American Journal of Transplantation, 20, 2058-2069.
Voortman, M.M., Greiner, P. and Mose, D.D. (2018) The Effect of Disease Modifying Therapies on CD62L Expression in Multiple Sclerosis. Multiple Sclerosis Journal—Experimental, Translational and Clinical, 4. https://doi.org/10.1177/2055217318800810
Gallon, L., Traitanon, O., Yu, Y., Shi, B., Leventhal, J.R., Miller, J., Mas, V. and Mathew, J.M. (2015) Differential Effects of Calcineurin and Mammalian Target of Rapamycin Inhibitors on Alloreactive Th1, Th17, and Regulatory T Cells. Transplantation, 99, 1774-1784. https://doi.org/10.1097/TP.0000000000000717
Issa, F., Hester, J., Goto, R., Nadig, S.N., Goodacre, T.E. and Wood, K. (2010) Ex Vivo-Expanded Human Regulatory T Cells Prevent the Rejection of Skin Allografts in a Humanized Mouse Model. Transplantation, 90, 1321-1327. https://doi.org/10.1097/TP.0b013e3181ff8772
Mathew, J.M., Jessica, H.V., LeFever, A., et al. (2018) A Phase I Clinical Trial with ex Vivo Expanded Recipient Regulatory T Cells in Living Donor Kidney Transplants. Scientific Reports, 8, Article No. 7428. https://doi.org/10.1038/s41598-018-25574-7