Role of Thymic Stromal Lymphopoietin (TSLP) in Palifermin-Mediated Immune Modulation and Protection from Acute Murine Graft-Versus-Host Disease

Abstract

Using the C57BL/6→(C57BL/6 × DBA/2)F 1 -hybrid model of acute graft-versus-host disease (GVHD), we previously showed that treating the donor mice with palifermin provides protection from morbidity and a shift from Th1 to Th2 cytokine production. To determine whether thymic stromal lymphopoietin (TSLP) is involved in palifermin-mediated immune modulation, we used donors from the following groups: (1) untreated wild-type donors, (2) palifermin-treated wild-type donors, (3) untreated TSLPR −/− donors, and (4) palifermin-treated TSLPR −/− donors. Survival in the recipients was 0%, 100%, 31%, and 0%, for groups 1-4, respectively, indicating that TSLP responsiveness is required for palifermin-mediated protection from GVHD. We also found that the increases in Th2 cytokine levels that are induced by palifermin treatment are obviated in TSLPR −/− donors, and that protection from GVHD (group 2) is associated with a higher percentage of CD4 + CD25 + Foxp3 + cells in the graft. Collectively, our findings show that when palifermin and TSLP act in concert, the predominant effect is protection in this model.

Immunomodulatory Effects of Palifermin (Recombinant Human Keratinocyte Growth Factor) in an SLE‐Like Model of Chronic Graft‐Versus‐Host Disease

“…Palifermin treatment did not significantly affect the percentage of CD4 + CD25 + Foxp3 + regulatory T cells in spleens from control, BDF1‐hybrid mice. The latter result is different from our previous findings involving untreated and palifermin‐treated C57BL/6 mice, which showed that palifermin induces a significant increase in the percentage of CD4 + CD25 + Foxp3 + regulatory T cells in the spleen [30].…”

“…Previous studies have shown that palifermin treatment induces both an increase in thymic output and expansion of CD4 + CD25 + FoxP3 + regulatory T cells in blood from mice with a C57BL/6 genetic background [29]. Our own experiments showed significantly higher percentages of CD4 + CD25 + FoxP3 + Treg in lymphoid grafts harvested from palifermin‐treated C57BL/6 donor mice, compared to grafts from untreated controls [30]. We wished to determine whether the percentages of Treg would be affected by palifermin treatment in this model of chronic, SLE‐like GVHD.…”

“…In this study, we were interested in determining whether palifermin treatment was indeed associated with increased TSLP expression. We were also interested in knowing whether palifermin treatment changes the percentage of CD4 + CD25 + FoxP3 + cells in the spleen, because palifermin treatment has been associated with increased percentages of CD4 + CD25 + FoxP3 + cells in other studies including our own [29, 30]. Lastly, we wished to study the effect of palifermin treatment on TGFβ levels, because this cytokine is known to play a pivotal role in the development of glomerulonephritis [31].…”