Association of Foxp3 regulatory gene expression with graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is characterized by an impairment of mechanisms that underlie the development of immunologic tolerance. Although the cytokine storm associated with GVHD leads to expression of cell surface markers on both effector and regulatory T cells, regulatory CD4 ؉ T cells that play an instrumental role in the maintenance of tolerance appear to uniquely express the Foxp3 transcriptional repressor. Foxp3 mRNA expression was significantly decreased in peripheral blood mononuclear cells from patients with either allogeneic GVHD or autologous GVHD compared with patients without GVHD. Expression of Foxp3 negatively correlated with the severity of GVHD but positively correlated with recent thymic emigrants. The results suggest that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms following transplantation. The decrease in regulatory mechanisms after transplantation appears to provide an environment permissive to the development of GVHD.

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

“…Fortunately, until now several studies have used PCR primer sets that amplify both Foxp3FL and Foxp3DE2 isoforms [25][26][27][28][29][30]. Nonetheless, interpretation of several other studies may be difficult since either the amplified Foxp3 region was not exactly reported [31][32][33][34] or only the full-length Foxp3 mRNA was amplified without any reasoning [35]. In conclusion, we think that the novel characteristics of human Foxp3 revealed in this study will improve the design and interpretation of clinical studies and may lead to a better understanding of the role of naturally Treg in human disease.…”

“…cDNA was synthesized using oligo(dT) primers and Superscript II Reverse Transcriptase (Invitrogen Life Technologies). The amounts of Foxp3FL and Foxp3DE2 and b-glucuronidase (GUS) were determined by amplifying the cDNA on an ABI prism 7900 cycler The primers and probe for Foxp3FL were previously described elsewhere [35]. The probe for Foxp3FL spans the junctional region between exon 2 and exon 3 [35].…”

“…The amounts of Foxp3FL and Foxp3DE2 and b-glucuronidase (GUS) were determined by amplifying the cDNA on an ABI prism 7900 cycler The primers and probe for Foxp3FL were previously described elsewhere [35]. The probe for Foxp3FL spans the junctional region between exon 2 and exon 3 [35]. To establish the isoform specificity, the probe for Foxp3DE2 was designed to span the junctional region between exon 1 and exon 3.…”

State-of-the-art acute and chronic GVHD treatment

“…In murine model, it has been demonstrated that the incidence and severity of cGVHD is higher in the absence of recipient Tregs, and the subsequent repletion with donor or host Tregs resulted in a protective effect [64]. In addition, monitoring of FOXP3 expression as a marker of Tregs showed Treg deficiency in cGVHD patients [65]. Several studies have suggested a possible collaboration of B and T cells in the pathogenesis of cGVHD.…”

Allogeneic intra-BM-BMT plus adult thymus transplantation from same donor has benefits for long-term survival even after sublethal irradiation or low-dose BM cell injection

“…As FoxP3 þ T reg cells have suppressive effects on GVHD, 19 the elevated proportion of FoxP3 þ T reg cells may be related to the low incidence of GVHD in the mice treated with IBM-BMT plus ATT. 23 There are two types of T reg cells: one is naturally occurring T reg (nT reg ) cells, which are derived from the thymus and the other is induced T reg (iT reg ) cells, which are induced in the periphery from FoxP3 À CD4 þ T cells. 24 It is likely that the former works predominantly in the mice treated with IBM-BMT plus ATT.…”