Patients with a high anti-inflammatory IL-10 production have been demonstrated to be protected from GVHD while patients with high TNF-alpha serum levels were more at risk for GVHD.
These findings provide for the first time a strong rationale for CD4<sup>IL-10</sup> cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies.
Type-1 regulatory T cells (Tr1 cells) and FoxP3<sup>+</sup> regulatory T cells (T<sub>regs</sub>) are predominant sources of IL-10 after SCT and the critical role of this cytokine in preventing GVHD is now established.
In the current study, we used reverse transcription (RT) polymerase chain reaction (PCR) to explore the mRNA expression of candidate inflammatory cytokines IL-1 alpha, IL-2, IL-4, IL-6, TNF-alpha, and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) and skin biopsies of allogeneic BMT patients with GVHD and controls.
Results of a previous study with human leukocyte antigen (HLA)-identical siblings showed individual and synergistic associations of single nucleotide polymorphisms in the promoter region of the recipient's IL10 gene and the donor's IL10 receptor beta (IL-10RB) gene with development of grades III-IV acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation.
In Conclusions, our findings suggest that IL-10 gene-modified DC-induced Tr1 cells could inhibit GVHD while maintaining Graft-versus-leukemia (GVL) through mediating the shift of Th1/Th2 cytokines in an allo-BMT mice model.
Furthermore, mice with clinical GVHD exhibited increases in the splenic human CD4<sup>+</sup>:CD8<sup>+</sup> T cell ratio, serum human interferon (IFN)-γ and intestinal human IL-17 expression compared to mice with subclinical GVHD.
The current study attempted to evaluate the association between IL-10 promoter gene polymorphism and transplant outcomes including the occurrence of chronic graft-versus-host disease (GVHD) and its clinical course during systemic immunosuppressive treatment (IST) among 60 recipients of cytokine-mobilized peripheral blood stem cell (PBSC) from HLA-matched sibling donors.
Recipients possessing longer IL-10(-1064) microsatellite alleles developed more severe acute GVHD: 22.3% of recipients possessing alleles 12 to 15 developed grade III to IV GVHD, versus 3.92% of those with smaller alleles (P <.01).
Patients who developed GVHD were characterized by a predominant pro-inflammatory response (IL-17A (10.02 vs 0.43pg/mL, p=0.006), TNF-α (54.57 vs 0.81pg/mL, p=0.001)), in contrast to a deficient suppressor profile (IL-10 (7.87 vs 41.37pg/mL, p=0.003)) and Tregs (0.95% vs 1.52%, p=0.004).
Furthermore, baricitinib (an inhibitor of Janus kinases 1 and 2 (JAK1/JAK2) downstream of IFNγR/IL6R) completely prevented GvHD; expanded regulatory T cells by preserving JAK3-STAT5 signaling; downregulated CXCR3 and helper T cells 1 and 2 while preserving allogeneic antigen-presenting cell-stimulated T-cell proliferation; and suppressed the expression of major histocompatibility complex II (I-Ad), CD80/86, and PD-L1 on host antigen-presenting cells.
In vivo assays showed that the serologic IL-10 level was evidently lower in GVHD than in non-GVHD patients, whereas the IL-1β, IFN-γ, and tumor necrosis factor-α levels were higher in GVHD patients.
Patients who developed moderate-to-severe acute GVHD had higher levels of TNF-alpha, IFN-gamma, IL-10 and sFas at 2 weeks post-SCT than in those with less GVHD.
Interleukin-10 Gene-Modified Dendritic Cell-Induced Type 1 Regulatory T Cells Induce Transplant-Tolerance and Impede Graft Versus Host Disease After Allogeneic Stem Cell Transplantation.
Proinflammatory cytokines released by host tissues during conditioning treatment and interferon gamma released from donor T cells play a major role in acute graft-versus-host disease (GVHD).