Graft-Versus-Host Disease Has Feature of T Cells, B Cells, and Systemic Sclerosis: A Study of Cytokine Expression in Histologically Matched Skin Biopsies
JM Wu, CJ Thoburn, J Wisell, AD Hess. Johns Hopkins Hospital, Baltimore, MD
Background: Graft-versus-host disease (GVHD) is the leading cause of non-relapse mortality after allogeneic bone marrow transplantation (BMT). Although the clinical presentation is well-characterized, much remains to be elucidated in the context of pathogenesis.
Design: Forty-seven skin biopsies representing GVHD grades 0, I, II, III, lichenoid (L), and sclerodermoid (S) were included from 31 patients with previous allogeneic BMT. Paraffin embedded tissue was harvested for cDNA. Real-time polymerase chain reaction assessed levels of the following markers: 1) T and B cells: CD3, CD20; 2) T cell subsets: Foxp3, TGF, IL-17; 3) cytokines associated with GVHD: interferon-gamma (IFN), IL-6; 4) factors implicated in systemic sclerosis: connective tissue growth factor (CTGF), allograft inflammatory factor-1 (AIF-1), and IL-13. Expression was correlated to grade, length of survival, and overall survival. Statistical analysis was performed using logistic and linear regressions.
Results: Levels of two markers significantly correlated with length of survival (TGF, corr coeff -23.6, p=0.009 and AIF-1, 14.0, p=0.035), while IFN approached statistical significance (-11.2, p=0.076). Levels of the same three markers also correlated with histologic grade by inspection, but did not reach statistical significance: IFN (0, 0.251, I, 0.599, II, 0.767, III, 0.496, L, 1.02, S, 0.382, p=0.097), TGF (0, 0.396, I, 0.544, II, 0.876, III, 0.570, L, 0.926, S, 173.6, p=0.13), and AIF-1 (0, 0.124, III, 0.006, L, 0.728, S, 0.718, p=0.527). No correlation to diagnosis or survival was found with CD3, Foxp3, IL-6, and CTGF. Expression of IL-17, IL-13, and CTGF was not detected. Lastly, expression of CD20 was observed in 2 of 9 patients with lichenoid GVHD.
Conclusions: We identify 3 markers that are not only potentially implicated in the progression from acute to chronic GVHD, but also modulate survival after transplantation, rendering IFN, AIF-1, and TGF promising therapeutic targets. A second target is identified in a subset of patients with lichenoid GVHD. The presence of CD20 positive B cells may correlate with the recently described group of chronic GVHD patients who are responsive to rituximab. Our findings challenge the notion that GVHD is a uniform, T cell driven process. Rather, there appears to be subsets within GVHD patients, whose disease manifestation rests with the interplay of T and B cells, as well as factors involved in systemic sclerosis.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 83, Monday Morning