Oral Communications 1
5.1 - Pretransplant Infusion Of Donor Stem Cells Opens Gateway To Tolerance Associated With Induction Of Regulatory T-Cells - Single Centre Experience In Living Donor Renal Transplantation
Presenter: Hargovind, Trivedi, Ahmedabad, India
Authors: Hargovind Trivedi1,2, Aruna Vanikar1,2, Shruti Dave1,2, Vivek Kute1,2, Himanshu Patel1,2, Manoj Gumber1,2, Pankaj Shah1,2
Pretransplant Infusion Of Donor Stem Cells Opens Gateway To Tolerance Associated With Induction Of Regulatory T-Cells - Single Centre Experience In Living Donor Renal Transplantation
Hargovind Trivedi1,2, Aruna Vanikar1,2, Shruti Dave1,2, Vivek Kute1,2, Himanshu Patel1,2, Manoj Gumber1,2, Pankaj Shah1,2
1Department of Nephrology and Transplantation Medicine, G. R. Doshi and K. M. Mehta Institute Of Kidney Diseases & Research Centre (IKDRC)- Dr. H.L. Trivedi Institute Of Transplantation Sciences (ITS), AHMEDABAD, India; 2Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute Of Kidney Diseases & Research Centre (IKDRC)- Dr. H.L. Trivedi Institute Of Transplantation Sciences (ITS), AHMEDABAD, India
Introduction: Transplantation tolerance is a state in which there is a lack of a destructive immune response by the recipient towards a well-functioning donor organ in the absence of maintenance immunosuppression and with a fully intact immune system. Limited long-term success has been achieved in transplant tolerance using hematopoietic stem cells (HSCs) and/or conditioning regimen. However dataregarding stem cell infusion (SCI) associated with tolerance induction in renal transplantation (RTx) is still sparse. We designed a prospective trial in a cohort of live-donor RTx (LDRT) patients subjected to pre-transplant SCI to test its tolerance promoting effects.
Material and methods: Ninety patients (81 males, 9 females) with mean age 32.2 years and donor-recipient HLA match, 2.81 who were subjected to pretransplant donor SCI of HSC and adipose tissue derived mesenchymal stem cells (AD-MSC) under non-myeloablative conditioning of cyclophosphamide, rabbit-antithymocyte globulin and rituximab with total lymphoid irradiation/ Bortezomib were included in the study. Commonest cause of end stage renal failure was chronic glomerulonephritis in 45.6%, chronic pyelonephritis in 25.6% and hypertensive nephropathy in 10%. Patients with diabetes, unwillingness, HIV, hepatitis C/B were excluded. Mean quantum of SC infused was 250 ml, with mean CD34+ 2.1 x 106/kg body-weight (KgBW), mean CD45-/90+ 4.4 x 104 /kgBW and CD45-/73+ 0.67 x 104/kgBW. There were no untoward effects of SCI/ conditioning. Immune monitoring included donor specific antibodies (DSA) by luminex assay and peripheral regulatory T-cell (pTregs) [CD4+CD25highCD127neg/low] by flow-cytometry. Peripheral blood lymphohematopoietic chimerism was evaluated by fluorescent in-situ hybridization in subset of patients with gender-mismatched donors.Initial maintenance immunosuppression was calcineurin-inhibitor based, to be discontinued with stable graft function and absence of rejection episodes. Graft biopsy was performed after 100 days of immunosuppression withdrawal in willing patients (protocol biopsy) or, for graft dysfunction. Rejections were treated by standard anti-rejection therapy followed by rescue immunosuppression.
Results: SCI was safe and no untoward effect of conditioning was observed. No patient/graft was lost. All immunosuppression except Prednisone has been successfully withdrawn for mean 2 years in all 90 patients. Their mean serum creatinine (SCr) of 1.4 mg/dL and p-Tregs, 3.63% has remained stable after withdrawal. DSA are absent in 32%, present in 54.4% and reports awaited in 13.3% patients. Chimerism was not always associated with clinical tolerance. Protocol biopsies were performed in 45 willing patients and 93.3% were unremarkable. Rescue immunosuppression was started in 6.7% patients after anti-rejection therapy. Their present mean SCr is 1.7 mg/dL.
Conclusion: Pre-transplant SCI leads to stable graft function with safe minimization of immunosuppression in living donor renal transplantation associated with induction of pTregs [CD4+CD25highCD127neg/low]. MSC may serve as novel, safe and effective immunomodulators in clinical transplantation.