Low-dose Interleukin-2 (IL-2) has been reported recently to increase Tregs and used to treat autoimmune disease including graft-versus-host disease (GVHD) after organ transplantation and HCV-related autoimmune vasculitis.
Here we wanted to determine if very low doses of Tregs generated using the "2-pathway" stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD.
Although in vivo IL-2 administration increased low Trp + Kyn iTreg persistence on adoptive transfer into immunodeficient mice given peripheral blood mononuclear cells to induce GVHD, IL-2-supported iTregs did not improve recipient survival.
However, the largest area under the receiver operating characteristic curve with 0.90 was observed when a 5-parameter biomarker score based on CD4<sup>+</sup> T cells, CD8<sup>+</sup> T cells, CD19<sup>-</sup> CD21<sup>+</sup> precursor B cells, CD4/CD8 T cell ratio, and soluble IL-2 receptor was used to predict GvHD.
Finally, in xeno-GVHD generated by human PBMCs transplanted into immunodeficient mice, low-dose IL-2 increased Treg frequencies but did neither control pro-inflammatory cytokine production by pathogenic Tcons, nor prevented GVHD.
Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning.
Two patients with established GVHD after OLT were treated with Basiliximab, a chimeric murine human monoclonal antibody which binds to the alpha-chain of interleukin-2 receptor (IL-2R).
Because IL-2 is a proinflammatory cytokine, we hypothesized that recipients with high-producer genotypes would have increased frequency of GVHD after allogeneic bone marrow transplantation (BMT).
IFN-gamma (4-fold), IL-2 (3-fold), and MIP-1alpha (44-fold) mRNA levels were also increased in GVHD-induced patients compared with healthy individuals.
Consistent with the PBMC data, IL-2 and IL-4 RNA were also more frequently detectable in skin biopsies with GVHD (n = 10): 70% of samples expressed IL-2 vs. 25% of normal controls (n = 8; P < 0.05); 60% had detectable IL-4 RNA vs. 0% of controls (P < 0.05).
These findings may indicate the important role of inflammatory cytokines such as IL-1 beta, IL-6 and TNF-alpha in the development of the clinical manifestation of GVHD and also may be indicative of the important role of IL-2 and the IL-2 receptor in allo response perhaps mainly as an autocrine effect.(ABSTRACT TRUNCATED AT 250 WORDS)
No cytokine mRNA was detected in the punch biopsy specimens except weak signals for IL-6 and IL-1 and GM-CSF in two normal donors and IL2-R in one patient with GvHD.