Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents

Abstract

We compared peripheral blood immunophenotyping in 31 adult liver transplant recipients on differing long-term immunosuppressive (IS) monotherapy with and without peri-transplantation alemtuzumab (AL) induction. All patients had been stable on monotherapy with either sirolimus (SRL) (n = 10) or without SRL (tacrolimus (TAC) (n = 10), mycophenolate mofetil (MMF) (n = 11)) for more than 6 months. Five-color flow cytometry for putative “regulatory” T and dendritic cells as well as serum assays for soluble HLA-G (sHLA-G) were performed. The SRL monotherapy group had significantly higher percentages of CD4+CD25high+ Foxp3+ T cells (1.3 ± 1.0) compared with the non-SRL group (0.7 ± 0.6) (p = 0.04). The SRL effect was even higher in a subset with prior AL induction and no prior hepatitis C or rejection (1.7 ± 0.2) compared with all other subgroups (0.7 ± 0.6) (p = 0.02). TAC patients showed significantly higher “regulatory” DC2:DC1 ratios (10 ± 7.6) compared with non-TAC patients (4.1 ± 2.3) (p = 0.04). Although sHLA-G levels appeared higher in TAC patients, the differences were not statistically significant. In conclusion, IS monotherapy provides an opportunity to investigate regulatory roles of individual agents. SRL maintenance and prior AL induction in subsets of patients appeared to show a regulatory T cell immunophenotype. However, TAC patients may have other regulatory characteristics, supporting the need for larger, prospective studies to clarify differences.

Favorable effects of alemtuzumab on allospecific regulatory T-cell generation

“…Moreover, a significant increase in Treg percentages in the peripheral blood of AL-treated renal transplant recipients persisted only if CNI therapy was withdrawn [9]. As have others [20], we have also demonstrated inhibitory effects of TAC on Treg generation in contrast to SRL, both in vitro and in vivo [12,15]. The long-term persistence of these effects in AL treated patients, however, still needs to be evaluated.…”

“…In addition, although we and others have reported clinical and ex vivo data on maintenance IS agents favoring higher Treg generation with SRL versus calcineurin inhibitors [11,12], it was questioned what the additional influence of AL would be with these maintenance agents i n vitro on this Treg subset. Consequently, we now report on (1) a proposed mechanism of the regulatory effects in MLR unique to AL, and (2) the contrasting effects in MLR of AL in combination with TAC versus SRL.…”

Expression of Soluble HLA-G Identifies Favorable Outcomes in Liver Transplant Recipients

“…Recent data in transplantation reported that although many immunosuppressive drugs (MMF, cyclosporine, and sirolimus) were found to have no effect on serum HLA-G level (34,35), other antiproliferative drugs such as everolimus (34) and tacrolimus (35) may be associated with the increase in serum HLA-G and better graft outcome. In our study, we did not detect correlation between immunosuppression drugs and serum HLA-G levels; thus, we believe that the findings of increased HLA-G levels in the drug-free tolerant patients relates largely to the clinical phenotype.…”

JC Virus T-Antigen DNA in Gastrointestinal Mucosa of Immunosuppressed Patients: A Prospective, Controlled Study

“…A further limitation is the lack of an objective biomarker of immune function to distinguish the so-called immunosuppressed subjects from controls. However, immunosuppression is difficult to quantify in this setting using a single assay, owing to the differing effects of each immunosuppressive drug on T-cell subsets and cytokine expression [42,43].…”