Impact of macrophage infiltration of skin lesions on survival after allogeneic stem cell transplantation: a clue to refractory graft-versus-host disease

Abstract

We retrospectively reviewed 104 biopsy specimens of previously untreated skin acute graft-versus-host disease (GVHD) within 100 days after allogeneic stem cell transplantation, and analyzed the relationship between types of infiltrating cells and clinical outcomes. Counting the total number of CD8 ؉ T cells, CD163 ؉ macrophages, and CD1a ؉ dendritic cells in 4 fields under original magnification IntroductionMacrophages are phagocytic cells with various abilities, such as phagocytosis, antigen-presenting, and secretion of cytokines. 1,2 Recently, it was revealed in human sequential biopsy data that recipient macrophages contributed to acute graft-versus-host disease (GVHD) by antigen-presenting and secreting cytokines, causing the activation and proliferation of CD8 ϩ T cells. 3 We focused on macrophage involvement in acute GVHD, especially on the relationship between the macrophage infiltration of skin lesions and refractory GVHD. MethodsBetween January 1997 and October 2007 at the Japanese Red Cross Nagoya First Hospital, we used skin biopsy specimens within 100 days after allogeneic stem cell transplantation (allo-SCT) of skin lesions clinically considered acute GVHD without any GVHD treatment from 104 patients who underwent allo-SCTs. We analyzed the relationship between types of infiltrating cells and clinical outcomes by counting the total number of CD8 ϩ T cells, CD163 ϩ macrophages, and CD1a ϩ dendritic cells in 4 fields of a skin biopsy specimen under original magnification ϫ200. Immunohistochemical analysis using paraffin sections was performed using monoclonal antibodies against CD8, CD163, and CD1a (Novocastra). CD163 is a member of the scavenger receptor cystein-rich superfamily and is an exclusive marker for macrophages, playing a major role in the scavenging components of damaged cells. [4][5][6][7] The endpoints of this study were the outcomes of acute GVHD and overall survival (OS). Acute GVHD was diagnosed and graded according to the consensus criteria. 8 We defined refractory GVHD as that exhibited by patients who had persistent lesions after primary steroid treatments. To establish parameters, we analyzed the numbers of infiltrating , disease risk (low vs high), human leukocyte antigen (HLA) disparity (match vs mismatch), donor source (related vs unrelated), graft source (bone marrow vs peripheral blood), age at allo-SCT (Յ 50 years vs Ͼ 50 years), conditioning regimen (conventional regimens vs reduced intensity regimens), and skin GVHD stage at biopsy (stages 1-2 vs stages 3-4). A significance level of P Ͻ .05 was used for all analyses, which were based on all data available as of August 31, 2008. Protocols were approved by the Japanese Red Cross Nagoya First Hospital's Institutional Review Board, and all patients provided informed consent in accordance with the Declaration of Helsinki. Table 1 summarizes the characteristics of patients and information gathered about GVHD. We divided patients into 4 groups according to the amount of infiltrating cells (FM and FT, 60.6%; MT and FM, 18.2%; MT...

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

“…42,43 One retrospective clinical study investigated the relationship between the types of infiltrating cells and the clinical outcomes of GVHD. 44 The number of macrophages that infiltrated skin lesions was shown to be a significant predictive factor for refractory GVHD and a poor prognosis, but the number of T cells was not. Macrophages may function as antigen-presenting cells during the initial stage of aGVHD, but also to provide pro-inflammatory cytokines to initiate the alloreactive adaptive immune response.…”

Acute graft-versus-host disease: a bench-to-bedside update

“…91 A recently described biomarker, ST2, the receptor for IL-33, 71 correlates with resistance to initial GVHD therapy and death. 92 During uncontrolled inflammation in refractory disease, additional rising biomarkers of epithelial cell death can be observed, 93 macrophages heavily infiltrate into the skin in response to continued inflammation, 94 and the chance of long-term survival drops dramatically. Survival is poor in steroid-resistant aGVHD, ;15% at 2 years.…”

Organ siderosis and hemophagocytosis during acute graft-versus-host disease

“…15 Due to the observation of the devastating course of patients with this presentation, alternative therapeutic strategies might be warranted, such as the potential use of etoposide.…”