Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings

Abstract

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).

Keywords: COVID - 19; chimerism; hematopoietic stem cell transplantation (HSCT); immunocompetence; kidney transplantation; tolerance.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Fehr, Hübel, de Rougemont, Abela, Gaspert, Güngör, Hauri, Helmchen, Linsenmeier, Müller, Nilsson, Riesterer, Scandling, Schanz and Cippà.

Figures

Figure 1

Overview over the trial protocol. Schematic overview over the trial protocol showing the timing of kidney and hematopoietic stem cell transplantation, immunosuppressive medication and monitoring with peripheral blood chimerism analyses and allograft biopsies.

Figure 2

Synopsis of renal function and proteinuria over time. The course of allograft function (serum creatinine, black dots) and proteinuria (protein/creatinine ratio, red dots) over time is shown for all three recipients. Dotted lines indicate time intervals of 6 and 12 months post-transplant and yearly thereafter. The hatched line indicates the time point of stop of all immunosuppressive treatment (IS). Asterisks indicate time points of allograft biopsies (see also Supplementary Table 1).

Figure 3

Allograft biopsy no 3 in patient 2. Allograft biopsy of patient 2 18 months post-transplant showing minimal glomerular alterations without signs of acute rejection. This biopsy was taken under minimal immunosuppressive therapy (cyclosporine A level at 13 ug/L), at the same time as the molecular microscope analysis shown in Figure 4.

Figure 4

Molecular microscope analysis of allograft biopsy no 3 in patient 2. In this analysis, an mRNA microarray of 60 genes was performed to arrive at a molecular diagnosis of T-cell-mediated, antibody-mediated or mixed rejection. This analysis was performed 18 months post-transplant under very low levels of cyclosporine monotherapy (trough level of 13 µg/L, Supplementary Figure 1) and showed a completely normal gene expression pattern as seen in normal kidneys from living donors (black dots are normal kidney, the green triangle represents our patient).

Figure 5

Synopsis of hematological parameters over time. The number of total leukocytes, neutrophils and lymphocytes is shown over time for all three recipients. Dotted lines indicate time intervals of 6 and 12 months post-transplant and yearly thereafter. The hatched line indicates the time point of stop of all immunosuppressive treatment (IS). Profound lymphopenia around the time of transplantation was seen in all three recipients. However, only patient 3 also experienced transient neutropenia, which resolved by 4 weeks post-transplant.

Figure 6

Synopsis of donor chimerism over time. The level of whole blood as well as lineage-specific donor chimerism is shown over time for all three recipients. Dotted lines indicate time intervals of 6 and 12 months post-transplant and yearly thereafter. The hatched line indicates the time point of stop of all immunosuppressive treatment (IS).