Tolerance protocol of living kidney transplant for developing countries through basic strategy of lymphocyte depletion

Abstract

End-stage kidney failure (ESKD) is a global issue where kidney replacement therapy imposes enormous economic burden to people of developing countries, in addition to the severe limitations to the availability of hemodialysis and peritoneal dialysis technique. The best option of kidney transplantation also requires lifelong combination immunosuppressive medicines, the cost of which is equally comparable to lifelong dialysis. A strategy of achieving transplant tolerance that requires minimum immunosuppressive medicines, although in experimental stage, also requires state-of-art technology with costly medicines and interventions. This is evidently beyond the reach of ESKD patients of developing countries. Hence, globally in developing countries, a need for an innovative but cost-effective tolerance protocol is a burning need for a successful transplant program. In brief, transplant tolerance is defined as a state of donor-specific unresponsiveness to the allograft antigens without the need for ongoing pharmacologic immunosuppression or with a minimal need. Current state-of-art techniques involves: (1) A state of hematological chimera, for complete tolerance; (2) Prope or partial tolerance where immune-reactive T-lymphocytes are inhibited using monoclonal antibodies; and (3) Chimeric antigen receptor for T-regulatory (T-reg) cell therapy using genetically engineered T-reg cells targeting specific T-lymphocyte receptors for inducing anergy. From our real-world experience in transplant management in post-transplant lympho-proliferative disorders (PTLD), we noticed frequently a drastic reduction in the need of immunosuppressive medicines following lympho-ablative therapy for PTLD. We recently published a case study on a real-world experience transplant case where we explained a partial or prope tolerance that developed after lymphocyte ablation therapy, following which the allograft was maintained with low dose dual standard immunosuppressive medicines. Based on this publication, we propose here an innovative tolerance protocol for living related low risk kidney transplantation for developing countries, in this opinion review.

Keywords: B and T lymphocytes depletion; Immunosuppressive medicines; Living renal transplant; Renal allograft; Tolerance protocol.

Figure 1

The mechanisms of tolerance and rejection. A: In fetal life, T-lymphocyte response as the clonal deletion of auto reactive T-lymphocytes in the thymus to the fetal antigens so that the organism is rendered self-tolerant to self-antigens, whereas after birth these changes to the state of clonal proliferation on exposure to exogenous antigens; B: In presence of allograft the immune reactive T-lymphocytes and subsequently B-lymphocytes, carry out the process of immune response and rejection as carried out by hematologic immune cells. Suppression of this mechanism leads to graft maintenance; C: Possible tolerance inducing strategies. APC: Antigen presenting cell; CD: Cluster differentiation; T-eff: T-effector; T-reg: T-regulator lymphocyte; CTLA4: Cytotoxic T-lymphocyte associated antigen 4; mAb: Monoclonal antibody; CAR-T: Chimeric antigen receptor encoded T-reg cell.

Figure 2

The tolerance protocol methodology for low immunogenic living kidney transplantation. A: Selection of Living donor and low immunogenic recipient; B: Sequence of peri-transplant protocol for B lymphocyte depletion, followed by transplantation and induction of immunosuppression. Subsequently, migration to tolerance regime.