Abrogation of the interactions between cxcr3 and its ligands MIG and IP-10 reduces the severity of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

Chemokines are important mediators in the development of Idiopathic Pneumonia Syndrome (IPS), a major cause of mortality after allogeneic (allo) stem cell transplantation (SCT). We hypothesized, that recruitment of donor T cells to the lung is dependent, at least in part, upon interactions between the chemokines MIG and IP-10 and their receptor CXCR3. CXCR3 is expressed on activated T cells; MIG and IP-10 can be induced in various cell types by IFNγ alone or in combination with TNFa or IL-1ß. We tested this hypothesis using an established murine SCT model wherein lethally irradiated bm1 mice receive SCT from either syngeneic (bm1) or allogeneic (B6Ly5.2) donors. MIG and IP-10 BAL levels were significantly elevated in allo recipients compared to syn controls at weeks 1 (MIG: 162.8 ± 37.6 vs 0; IP-10: 41.1 ± 4.2 vs 0 pg/ml) and 4 (MIG: 153.5 ± 41.7 vs 21.6 ± 9.0; IP-10: 202.0 ± 61.1 vs 3.8 ± 0.9 pg/ml) and correlated with the infiltration of donor T cells into the lung. To examine the effect of these chemokines on T cell recruitment, we treated allogeneic recipients with polyclonal antibodies (Abs) against MIG and IP-10 or control from day 0 until day 28. Lung pathology at day 28 was significantly decreased in the Ab-treated animals and was associated with significantly decreased numbers of total cells, CD8+T cells and TNFa levels in the BAL fluid (table 1). MIG/IP-10 neutralization also resulted in reduced damage to the GI tract by week 1 and 4 (table 1), whereas liver pathology was unaffected. Clinical GVHD scores were also lower in Ab-treated animals at weeks 5 and 6 after SCT and correlated with a reduction in mortality during this time. In a final set of experiments, we used CXCR3−/− mice as allo SCT donors and found that mice receiving CXCR3−/− cells had decreased lung injury compared to allo wild-type controls at week 4 as measured by BAL cellularity (1.2 ± 0.1 vs. 2.5 ± 0.4 mio), CD8+T cells (0.06 ± 0.01 vs. 0.17 ± 0.03 mio) and TNFa levels (9.0 ± 1.8 vs. 33.4 ± 8.0 pg/ml). In conclusion, our data demonstrate, that interactions between the chemokines MIG and IP-10 and their receptor CXCR3 are important for donor T cell recruitment into the lung and the development of IPS. Approaches focusing on the abrogation of these interactions may prove successful in preventing or treating this serious complication after allogeneic SCT. TableLung Path.Total BAL Cells (mio.)BAL CD8+ Cells (mio.)BAL TNFα (pg/mL)Gut Path. Week 1Gut Path. Week 4Syn+ctrl1.4±0.40.6±0.040.04±0.0036.9±0.18.0±0.613.0±1.0Allo+ctrl5.3±0.41.6±0.380.19±0.04720.8±3.223.2±1.619.5±2.3Allo+anti-MIG/IP-103.5±0.4∗P < .05; (+) P = .06.0.4±0.04∗P < .05; (+) P = .06.0.02±0.002∗P < .05; (+) P = .06.7.8±3.0∗P < .05; (+) P = .06.13.8±1.6∗P < .05; (+) P = .06.13.2±1.6 (+)∗ P < .05; (+) P = .06. Open table in a new tab