Acute graft-versus-host disease (GVHD) occurs in 40% to 60% of recipients of partially matched umbilical cord blood transplantation (UCBT). In a phase I study, adoptive transfer of expanded CD4+CD25+Foxp3+ natural regulatory T cells (nTregs) resulted in a reduced incidence of grade II-IV acute GVHD. To investigate potential mechanisms responsible for the reduced GVHD risk, we analyzed peripheral blood mononuclear cell mRNA expression of a tolerance gene set previously identified in operation- tolerant kidney transplant recipients, comparing healthy controls and patients who received nTregs and those who did not receive nTregs with and without experiencing GVHD. Samples from patients receiving nTregs regardless of GVHD status showed increased expression of Foxp3 expression, as well as B cell-related tolerance marker. This was correlated with early B cell recovery, predominately of naïve B cells, and nearly normal T cell reconstitution. CD8+ T cells showed reduced signs of activation (HLA-DR+ expression) compared with conventionally treated patients developing GVHD. In contrast, patients with GVHD had significantly increased TLR5 mRNA expression, whereas nTreg-treated patients without GVHD had reduced TLR5 mRNA expression. We identified Lin-HLADR-CD33+CD16+ cells and CD14++CD16- monocytes as the main TLR5 producers, especially in samples of conventionally treated patients developing GVHD. Taken together, these data reveal interesting similarities and differences between tolerant organ and nTreg-treated hematopoietic stem cell transplantation recipients.
Bibliographical noteFunding Information:
Financial disclosure: Supported in part by Deutsche Forschungsgemeinschaft Grants SFB650 and TR52 (to B.S.); National Institutes of Health Grants R01 HL56067 , AI 34495 , and P01 AI056299 (to B.R.B.); National Cancer Institute Grant P01 CA067493 (to B.R.B., J.E.W., and J.S.M.); National Heart, Lung, and Blood Institute Grant N01 HB037164 (to J.E.W. and J.S.M.); the Children's Cancer Research Fund (B.R.B., K.J.L., J.E.W., J.M.C., J.S.M., and M.R.V.); Leukemia and Lymphoma Society Scholar in Clinical Research Award 2417-11 (to C.G.B.); and the Masonic Cancer Center.
- Graft-versus-host disease
- Hematopoetic stem cell transplantation
- Regulatory T cells
- Toll-like receptor