The tissue expression of cytokines in human acute cutaneous graft-versus-host disease

Although acute graft-versus-host disease (GVHD) is a common complication after allogeneic bone marrow transplantation (BMT), the specific pathophysiology of tissue damage has not been elucidated. We have previously described an infiltrate of CD2+, CD8+, alpha/beta receptor+ T lymphocytes, and the upregulation of ICAM-1 in tissues with acute GVHD. We hypothesized that these infiltrating lymphocytes may secrete cytokines that could contribute to tissue damage. In the current study, we used reverse transcription (RT) polymerase chain reaction (PCR) to explore the mRNA expression of candidate inflammatory cytokines IL-1 alpha, IL-2, IL-4, IL-6, TNF-alpha, and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) and skin biopsies of allogeneic BMT patients with GVHD and controls. In post-BMT control PBMC (n = 10); IL-2 RNA was infrequent (20% of samples) but was significantly more frequently detectable (71%; P < 0.05) after development of acute GVHD (n = 7). IL-4 expression was also more common in PBMC from patients with acute GVHD (57% vs. 30%; P < 0.05). Consistent with the PBMC data, IL-2 and IL-4 RNA were also more frequently detectable in skin biopsies with GVHD (n = 10): 70% of samples expressed IL-2 vs. 25% of normal controls (n = 8; P < 0.05); 60% had detectable IL-4 RNA vs. 0% of controls (P < 0.05). IFN-gamma detectability (40% vs. 12%; P < 0.05) was also more frequent in GVH skin. For both PBMC and skin, IL-1 alpha expression was infrequent in GVHD and controls, whereas TNF-alpha and IL-6 were expressed in nearly all samples. These data suggest that upregulated expression of IL-2, IL-4, and IFN-gamma may be part of the inflammatory cascade of human acute GVHD, while IL-1 alpha, TNF-alpha, and IL-6 are not discriminatory for the inflammation observed at the time of initial GVHD diagnosis.