Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers

Abstract

We previously described early results of a non-chimeric operational tolerance protocol in HLA identical living donor renal transplants and now update these results. Recipients given alemtuzumab, tacrolimus/MPA with early sirolimus conversion were multiply infused with donor hematopoietic CD34+ stem cells. Immunosuppression was withdrawn by 24 months. Twelve months later operational tolerance was confirmed by rejection-free transplant biopsies. Five of the first 8 enrollees were initially tolerant one year off immunosuppression. Biopsies of 3 others after total withdrawal showed Banff 1A acute cellular rejection without renal dysfunction. With longer follow-up including 5 year post-transplant biopsies 4 of the 5 tolerant recipients remain without rejection while one developed Banff 1A without renal dysfunction. We now add 7 new subjects (2 operationally tolerant), and demonstrate time-dependent increases of circulating CD4+CD25+++CD127−FOXP3+ Tregs vs. losses of Tregs in non-tolerant subjects (p< 0.001). Gene expression signatures, developed using global RNA expression profiling of sequential whole blood and protocol biopsy samples, were highly associative with operational tolerance as early as 1 year post-transplant. The blood signature was validated by an external ITN data set. Our approach to non-chimeric operational HLA identical tolerance reveals association with Treg immunophenotypes and serial gene expression profiles.

A composite score associated with spontaneous operational tolerance in kidney transplant recipients

“…We applied the cSoT in a trial of tolerance induction in which 15 renal recipients of HLA-identical living donor siblings were followed up for 5 years after transplantation 9, 10 . The protocol consisted in infusions of donor hematopoietic CD34 + stem cells with a conditioning regimen and immunosuppression was withdrawn 2 years after transplantation.…”

Current State of Tolerance: The Holy Grail

“…Each calf has a proportion of red cells belonging genetically to itself and that belonging to the twin. They were also shown in subsequent experiments to be able to tolerate skin grafts from each other [19]. This led to further experiments by Anderson et al, in 1951 where skin grafts were used to distinguish monozygotic from dizygotic twins [20].…”

“…Transplantation between genetically identical monozygotic twins has shown remarkable results of tolerance [19]. However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance [19][20][21][22][23].…”

“…However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance [19][20][21][22][23]. …”

Hematopoietic stem cells and solid organ transplantation

“…Table 2 provides a listing of these studies in which bone marrow infusions containing HSCs have been used to induce tolerance to solid organ transplants in humans (36–44). Other studies have certainly also been done support the importance of donor specific transfusions for transplant tolerance, including the Trivedi group in Hyderabad (45) and further studies on genomic markers is providing new information from groups that have been working in this area for some time (46, 47). …”