Increased T-bet+ cytotoxic effectors and type I interferon–mediated processes in chronic graft-versus-host disease of the oral mucosa

109

Key Points• Distinct T-cell patterns characterize the acute and chronic forms of cutaneous GVHD.• Increased TSLP expression is an indicator of acute cutaneous GVHD development.Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n 5 25), clGVHD (n 5 17), and csGVHD (n 5 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n 5 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4 1 T cells.Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-g-and IL-17-producing CD8

Section: Cells In Cutaneous Gvhd 297supporting

confidence: 79%

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Brüggen

Klein

Greinix³

et al. 2014

109

“…13 In both human and mouse autoimmune disease studies, the binding of CXCL9 to CXCR3 promotes lymphocyte migration to inflamed tissues. 17,18 CXCR3 has also been shown to be critical for the recruitment of alloreactive T cells in aGVHD, 19,20 whereas CXCL9 has been shown to be elevated in tissue samples from patients with oral, 21 ocular, 22 and cutaneous 23 cGVHD. We found that the plasma of patients with newly diagnosed cGVHD, but not established cGVHD, contains higher concentrations of CXCL9 than patients without cGVHD.…”

Section: Discussionmentioning

confidence: 99%

Plasma CXCL9 elevations correlate with chronic GVHD diagnosis

Kitko

Levine

Storer

et al. 2014

• Plasma concentrations of CXCL9 are elevated at the onset of cGVHD diagnosis, but not in patients with cGVHD for more than 3 months.• Plasma concentrations of CXCL9 are impacted by immunosuppressive therapy.There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential enzyme-linked immunosorbent assay to compare 17 patients with treatment-refractory de novo-onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify 5 candidate proteins that distinguished cGVHD from no cGVHD: CXCL9, IL2Ra, elafin, CD13, and BAFF. We then assessed the discriminatory value of each protein individually and in composite panels in a validation cohort (n 5 109). CXCL9 was found to have the highest discriminatory value with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval, 0.74-0.91). CXCL9 plasma concentrations above the median were associated with a higher frequency of cGVHD even after adjustment for other factors related to developing cGVHD including age, diagnosis, donor source, and degree of HLA matching (71% vs 20%; P < .001). A separate validation cohort from a different transplant center (n 5 211) confirmed that CXCL9 plasma concentrations above the median were associated with more frequent newly diagnosed cGVHD after adjusting for the aforementioned factors (84% vs 60%; P 5 .001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD. (Blood. 2014;123(5):786-793)

“…43 The ability of this cytokine to induce fibrotic responses within fibroblasts and scleroderma in the absence of SOCS3 is thus not surprising. In contrast IFN␥ generation after BMT is almost entirely derived from the donor T cell and, although the mechanism by which this cytokine may promote fibrosis is unclear, the association has been made with clinical chronic GVHD 44 and systemic sclerosis. 45 Although animal studies have shown that autoimmune "chronic" GVHD may occur in a Th1-dependent fashion, 46 these studies do not induce the fibrosis that is characteristic of clinical chronic GVHD.…”

Section: Socs3 Regulates Gvhd 293mentioning

confidence: 99%

SOCS3 regulates graft-versus-host disease

Hill

Kuns

Raffelt

et al. 2010

Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3 ؊/⌬vav donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3 ؊/⌬LysM and SOCS3 ؊/⌬lck donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3 ؊/⌬lck donor T cells underwent enhanced alloantigendependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-␥ (IFN␥) after SCT. The enhanced capacity of the SOCS3 ؊/⌬lck donor T cell to induce acute GVHD was dependent on IFN␥ but independent of IL-10 or IL-17. Surprisingly, SOCS3 ؊/⌬lck donor T cells also induced severe, transforming growth factor ␤-and IFN␥-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD. (Blood. 2010;116(2): 287-296)