Chemokine gene expression during Pneumocystis carinii-driven pulmonary inflammation

Severe combined immunodeficient (SCID) mice lack functional lymphocytes and therefore develop Pneumocystis carinii pneumonia. However, when infected S CID mice are immunologically reconstituted with congenic spleen cells, a pr otective inflammatory cascade is initiated. Proinflammatory cytokines are p roduced, and lymphocytes and macrophages are recruited specifically to alve olar sites of infection. Importantly, uninfected regions of the lung remain free from inflammatory involvement, suggesting that there are specific mec hanisms that limit inflammation in the infected lung. Therefore, to determi ne whether chemokines are involved in targeting the P. carinii-driven infla mmatory response, steady-state mRNA levels of several chemokines were measu red in the lungs of both reconstituted and nonreconstituted P. carinii-infe cted SCID mice. Despite significant organism burdens in the lungs of 8- and 10-week-old SCID mice, there was no evidence of elevated chemokine gene ex pression, which is consistent with the lack of an inflammatory response in these animals. However, when 8-week-old infected SCID mice were immunologic ally reconstituted, signs of focal pulmonary inflammation were observed, an d levels of RANTES, MCP-1, lymphotactin, MIP-1 alpha, MIP-1 beta, and MIP-2 mRNAs were all significantly elevated. Chemokine mRNA abundance was elevat ed at day 10 postreconstitution (PR), was maximal at day 12 PR, and returne d to baseline by day 22 PR. In situ hybridization demonstrated that during the peak of inflammation, RANTES gene expression was localized to sites of inflammatory cell infiltration and P. carinii infection. Thus, these observ ations indicate that chemokines play a role in the focal targeting of infla mmatory cell recruitment to sites of P, carinii infection after the passive transfer of lymphocytes to the host.