17 research outputs found
Analyses and Correlation of Pathologic and Ocular Cutaneous Changes in Murine Graft versus Host Disease
Graft versus host disease (GVHD) is initiated by donor allo-reactive T cells activated against recipient antigens. Chronic GVHD (cGVHD) is characterized by immune responses that may resemble autoimmune features present in the scleroderma and Sjogren’s syndrome. Unfortunately, ocular involvement occurs in approximately 60–90% of patients with cGVHD following allo-hematopoietic stem cell transplants (aHSCT). Ocular GVHD (oGVHD) may affect vision due to ocular adnexa damage leading to dry eye and keratopathy. Several other compartments including the skin are major targets of GVHD effector pathways. Using mouse aHSCT models, the objective was to characterize cGVHD associated alterations in the eye and skin to assess for correlations between these two organs. The examination of multiple models of MHC-matched and MHC-mismatched aHSCT identified a correlation between ocular and cutaneous involvement accompanying cGVHD. Studies detected a “positive” correlation, i.e., when cGVHD-induced ocular alterations were observed, cutaneous compartment alterations were also observed. When no or minimal ocular signs were detected, no or minimal skin changes were observed. In total, these findings suggest underlying cGVHD-inducing pathological immune mechanisms may be shared between the eye and skin. Based on the present observations, we posit that when skin involvement is present in aHSCT patients with cGVHD, the evaluation of the ocular surface by an ophthalmologist could potentially be of value
A critical role for donor-derived IL-22 in cutaneous chronic GVHD
Graft-versus-host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end-organ dysfunction and opportunistic infection. The role of interleukin (IL)-17 and IL-22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T cell-derived IL-22 significantly exacerbates cutaneous chronic GVHD and that IL-22 is produced by highly inflammatory donor CD4āŗ T cells posttransplantation. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL-22āŗ Th17 cells. Donor Th22 and IL-22āŗ Th17 cells share a similar IL-6-dependent developmental pathway, and while Th22 cells arise independently of the IL-22āŗ Th17 lineage, IL-17 signaling to donor Th22 directly promotes their development in allo-SCT. Importantly, while both IL-22 and IL-17 mediate skin GVHD, Th17-induced chronic GVHD can be attenuated by IL-22 inhibition in preclinical systems. In the clinic, high levels of both IL-17A and IL-22 expression are present in the skin of patients with GVHD after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.Kate H. Gartlan, Hemamalini Bommiasamy, Katelyn Paz, Andrew N. Wilkinson, Mary Owen, Dawn K. Reichenbach, Tatjana Banovic, Kimberly Wehner, Faith Buchanan, Antiopi Varelias, Rachel D. Kuns, Karshing Chang, Yuri Fedoriw, Thomas Shea, James Coghill, Michael Zaiken, Maximilian W. Plank, Paul S. Foster, Andrew D. Clouston, Bruce R. Blazar, Jonathan S. Serody, Geoffrey R. Hil
Targeting PI3KĪ“ function for amelioration of murine chronic graftāversusāhost disease
Chronic graftāversusāhost disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)ā17 cells and germinal center (GC)āpromoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositideā3ākinaseāĪ“ (PI3KĪ“), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3KĪ“ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3KĪ“ signaling for function and survival. Although B cells rely on PI3KĪ“ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3KĪ“ kinaseādead mutant donor bone marrowāderived GC B cells still supported BO cGVHD generation. A PI3KĪ“āspecific inhibitor, compound GSā649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1ādependent and Th17āassociated scleroderma model, GSā649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)āapproved PI3KĪ“ inhibitors for cGVHD therapy in patients