Kinetics of Homeostatic Proliferation and Thymopoiesis after rATG Induction Therapy in Kidney Transplant Patients

Background Lymphocyte-depleting therapy is associated with long-lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies. The mechanisms of T-cell repopulation and their posttransplantation kinetics are not fully understood. Methods We studied thymopoiesis by CD31+ naïve T cells (recent thymic emigrants) and homeostatic proliferation by Ki-67+ T cells in rabbit antithymocyte globulin (rATG)–treated patients the first 6 months after transplantation. Patients receiving basiliximab or no induction therapy served as controls. Results At 6 months after transplantation, T-cell numbers were lower than before transplantation in rATG-treated patients, whereas T-cell numbers remained stable in both control groups. In this time period, thymopoiesis was similar between the three treatment groups; CD8+ T cells showed the highest percentage of recent thymic emigrants. At month 1, percentages of Ki-67+ naïve and memory CD4+ and CD8+ T cells were the highest in rATG-treated patients, but these percentages declined in the months thereafter. When CD31 was used to distinguish between cytokine- and antigen-driven proliferation in naïve T cells, we found evidence for cytokine-dependent proliferation. Cytokine-dependent proliferation was also shown by in vivo increased percentages of phosphorylated STAT5 and high expression levels of the interleukin-7 receptor-&agr; and interleukin-15 receptor-&agr; by T cells. Conclusion These findings demonstrate that, in the first month after rATG therapy, cytokine-induced homeostatic proliferation is involved in T-cell repopulation of both naïve and memory T cells. At later time points, the contribution of homeostatic proliferation diminished, which explains the observed incomplete T-cell recovery.

[1]  W. Weimar,et al.  The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients. , 2012, Transplant immunology.

[2]  X. Li,et al.  Memory T cells and their exhaustive differentiation in allograft tolerance and rejection , 2012, Current opinion in organ transplantation.

[3]  W. Baldwin,et al.  Evaluation of Alloreactivity in Kidney Transplant Recipients Treated with Antithymocyte Globulin Versus IL‐2 Receptor Blocker , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  P. Tiberghien,et al.  Thymic function, anti-thymocytes globulins, and cancer after renal transplantation. , 2011, Transplant immunology.

[5]  E. Wherry.  T cell exhaustion , 2011, Nature Immunology.

[6]  J. Bromberg,et al.  Immune Reconstitution Following Rabbit Antithymocyte Globulin , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  M. Deschamps,et al.  Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation. , 2010, Journal of the American Society of Nephrology : JASN.

[8]  P. Price,et al.  CD31 (PECAM‐1) is a marker of recent thymic emigrants among CD4+ T‐cells, but not CD8+ T‐cells or γδ T‐cells, in HIV patients responding to ART , 2010, Immunology and cell biology.

[9]  A. Şener,et al.  Memory T‐Cell Predominance Following T‐Cell Depletional Therapy Derives from Homeostatic Expansion of Naive T Cells , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[10]  R. Pujol-Borrell,et al.  Immunological Senescence and Thymic Function in Transplantation , 2009, Transplantation.

[11]  W. Weimar,et al.  The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[12]  A. Thiel,et al.  Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. , 2009, Blood.

[13]  R. Gress,et al.  T cell immune reconstitution following lymphodepletion. , 2007, Seminars in immunology.

[14]  D. Brennan,et al.  Rabbit antithymocyte globulin versus basiliximab in renal transplantation. , 2006, The New England journal of medicine.

[15]  P. Friend,et al.  Recipient Memory-Like Lymphocytes Remain Unresponsive to Graft Antigens After CAMPATH-1H Induction with Reduced Maintenance Immunosuppression , 2006, Transplantation.

[16]  A. Kirk.  Induction Immunosuppression , 2006, Transplantation.

[17]  F. Berthoux,et al.  Long-term kinetic of T-lymphocyte subsets in kidney-transplant recipients: influence of anti-T-cell antibodies and association with posttransplant malignancies. , 2005, Transplantation.

[18]  A. Kirk,et al.  Immunocompetent T‐Cells with a Memory‐Like Phenotype are the Dominant Cell Type Following Antibody‐Mediated T‐Cell Depletion , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[19]  K. Shuai,et al.  Regulation of JAK–STAT signalling in the immune system , 2003, Nature Reviews Immunology.

[20]  D. Ho,et al.  Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. , 2002, Blood.

[21]  P. Tiberghien,et al.  Lymphocyte subsets and assessment of cancer risk in renal transplant recipients , 2002, Transplant international : official journal of the European Society for Organ Transplantation.

[22]  Andreas Radbruch,et al.  Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral Blood , 2002, The Journal of experimental medicine.

[23]  J. Revillard,et al.  MECHANISMS INVOLVED IN ANTITHYMOCYTE GLOBULIN IMMUNOSUPPRESSIVE ACTIVITY IN A NONHUMAN PRIMATE MODEL 1 , 2001, Transplantation.

[24]  S. Jameson,et al.  Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo , 2000, Nature Immunology.

[25]  R. Ahmed,et al.  Cutting Edge: Naive T Cells Masquerading as Memory Cells , 2000, The Journal of Immunology.

[26]  R. Collins,et al.  Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution , 2000, The Lancet.

[27]  R. Koup,et al.  Generation of functional thymocytes in the human adult. , 1999, Immunity.

[28]  Louis J. Picker,et al.  Changes in thymic function with age and during the treatment of HIV infection , 1998, Nature.

[29]  P. Carron,et al.  CD4 lymphocytopenia in long-term renal transplant recipients. , 1998, Transplantation proceedings.

[30]  H. Sprenger,et al.  Persistent long-term changes in lymphocyte subsets induced by polyclonal antibodies. , 1997, Transplantation.

[31]  J. Berlin,et al.  Effect of anti-lymphocyte induction therapy on renal allograft survival: a meta-analysis. , 1997, Journal of the American Society of Nephrology : JASN.

[32]  S. Steinberg,et al.  Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. , 1995, The New England journal of medicine.

[33]  N. K. Tchaoa,et al.  Lymphodepletion and Homeostatic Proliferation : Implications for Transplantation , 2012 .

[34]  C. Mackall,et al.  Age-dependent incidence, time course, and consequences of thymic renewal in adults. , 2005, The Journal of clinical investigation.

[35]  J. Craig,et al.  Interleukin 2 receptor antagonists for kidney transplant recipients. , 2004, The Cochrane database of systematic reviews.

[36]  B. Haynes,et al.  The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. , 2000, Annual review of immunology.