A Clinical Trial With Adoptive Transfer of Ex Vivo-induced, Donor-specific Immune-regulatory Cells in Kidney Transplantation—A Second Report

Background. Although the outcome of kidney transplantation (KTx) has improved, various adverse effects of immunosuppressants and chronic rejection aggravate the long-term prognosis of patients. Therefore, the induction of immune tolerance may be an effective therapeutic strategy. Methods. A clinical trial aiming at immune tolerance induction was conducted in kidney transplant recipients from HLA mismatched living donors by infusing autologous donor-specific regulatory T cells (Treg). To obtain Treg, recipient’s peripheral blood mononuclear cells were cocultured with irradiated donor cells in the presence of anti-CD80/CD86 monoclonal antibody for 2 weeks. For preconditioning, splenectomy + cyclophosphamide (CP) was employed in the first series (group A; n = 9). In group B, splenectomy was substituted by preadministration of rituximab (group B; n = 3). In the latest cases, rituximab + rabbit antithymocyte globulin was administered instead of cyclophosphamide (group C; n = 4). Twelve days after KTx, the cultured cells were intravenously infused, and immunosuppressants were gradually tapered thereafter. Results. Although mixed lymphocyte reaction was remarkably suppressed in a donor-specific fashion, 6 out of 9 patients from group A, 1 out of 3 from group B, and 1 out of 4 from group C developed acute rejection within 1 year after KTx. Complete cessation of immunosuppression was not achieved, and a small dose of immunosuppressants was continued. Conclusions. The adoptive transfer of autologous ex vivo-expanded Treg is 1 of the options to possibly induce alloimmune hyporesponsiveness. However, in the present study, further regimen optimization is still required and should be the focus of future investigations.

[1]  R. Kornbluth,et al.  Generation and Characterization of Alloantigen-Specific Regulatory T Cells For Clinical Transplant Tolerance , 2018, Scientific Reports.

[2]  M. Sarwal,et al.  Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants , 2017, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  K. Okumura,et al.  A Clinical Trial Aiming at Tolerance Induction by Adoptive Transfer of Ex Vivo-Induced, Donor-Specific Treg-Like Cells in Clinical Kidney Transplantation , 2017 .

[4]  S. Todo,et al.  A pilot study of operational tolerance with a regulatory T‐cell‐based cell therapy in living donor liver transplantation , 2016, Hepatology.

[5]  R. Colvin,et al.  Long‐Term Results in Recipients of Combined HLA‐Mismatched Kidney and Bone Marrow Transplantation Without Maintenance Immunosuppression , 2014, American Journal of Transplantation.

[6]  K. Wood,et al.  Harnessing Regulatory T Cells for Clinical Use in Transplantation: The End of the Beginning , 2014, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  Qizhi Tang,et al.  Regulatory T-cell therapy in transplantation: moving to the clinic. , 2013, Cold Spring Harbor perspectives in medicine.

[8]  M. Abecassis,et al.  Tolerance Induction in HLA Disparate Living Donor Kidney Transplantation by Donor Stem Cell Infusion: Durable Chimerism Predicts Outcome , 2013, Transplantation.

[9]  E. Geissler.  The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells , 2012, Transplantation research.

[10]  M. Sarwal,et al.  Tolerance and Withdrawal of Immunosuppressive Drugs in Patients Given Kidney and Hematopoietic Cell Transplants , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  M. Abecassis,et al.  Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation , 2012, Science Translational Medicine.

[12]  J. Wagner,et al.  Generation and Large‐Scale Expansion of Human Inducible Regulatory T Cells That Suppress Graft‐Versus‐Host Disease , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  R. Lechler,et al.  Human Regulatory T Cells with Alloantigen Specificity Are More Potent Inhibitors of Alloimmune Skin Graft Damage than Polyclonal Regulatory T Cells , 2011, Science Translational Medicine.

[14]  J. Wagner,et al.  Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. , 2011, Blood.

[15]  D. Farber,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.

[16]  J. Myśliwska,et al.  First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. , 2009, Clinical immunology.

[17]  K. Brown,et al.  Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection1 , 2008, The Journal of Immunology.

[18]  E. Engleman,et al.  Tolerance and chimerism after renal and hematopoietic-cell transplantation. , 2008, The New England journal of medicine.

[19]  V. Sharma,et al.  HLA-mismatched renal transplantation without maintenance immunosuppression. , 2008, The New England journal of medicine.

[20]  R. Lechler,et al.  In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. , 2007, Blood.

[21]  M. Sayegh,et al.  A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. , 2006, Journal of the American Society of Nephrology : JASN.

[22]  J. Markmann,et al.  Accelerated Memory Cell Homeostasis during T Cell Depletion and Approaches to Overcome It , 2006, The Journal of Immunology.

[23]  M. Kimikawa,et al.  Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates. , 2005, The Journal of clinical investigation.

[24]  T. Asahara,et al.  Low Incidence of Acute Rejection after Living-Donor Liver Transplantation: Immunologic Analyses by Mixed Lymphocyte Reaction using a Carboxyfluorescein Diacetate Succinimidyl Ester Labeling Technique , 2005, Transplantation.

[25]  B. Levine,et al.  In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. , 2004, Blood.

[26]  Jeffrey A. Bluestone,et al.  In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes , 2004, The Journal of experimental medicine.

[27]  N. Câmara,et al.  Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. , 2003, Blood.

[28]  M. Roncarolo,et al.  Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function , 2001, The Journal of experimental medicine.

[29]  K. Okumura,et al.  Anergic T cells generated in vitro suppress rejection response to islet allografts. , 2000, Transplantation.

[30]  R. Lechler,et al.  Anergic T cells act as suppressor cells in vitro and in vivo , 1999, European journal of immunology.

[31]  R. Gingrich,et al.  Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. , 1995, Bone marrow transplantation.

[32]  R. Lechler,et al.  Anergic T cells as suppressor cells in vitro. , 1994, Science.