SPONTANEOUS ELABORATION OF TRANSFORMING GROWTH-FACTOR-BETA SUPPRESSESHOST-DEFENSE AGAINST BACTERIAL-INFECTION IN AUTOIMMUNE MRL LPR MICE/

Infection with gram-negative and gram-positive bacteria remains a lead ing cause of death in patients with systemic lupus erythematosis (SLE) , even in the absence of immunosuppressive therapy. To elucidate the m echanisms that underly the increased risk of infection observed in pat ients with systemic autoimmunity, we have investigated host defense ag ainst bacterial infection in a murine model of autoimmunity, the MRL/M p-lpr/lpr (MRL/lpr) mouse. Our previous study implicated transforming growth factor beta (TGF-beta) in a novel acquired defect in neutrophil function in MRL/lpr but not congenic MRL/Mp-+/+ (MRL/n) mice (Gresham , H.D., C.J. Ray, and F.K. O'Sullivan. 1991. J. Immunol, 146:3911.) We hypothesized from these observations that MRL/lpr mice would have def ects in host defense against bacterial infection and that they would h ave constitutively higher local and systemic levels of active TGF-beta which would be responsible, at least in part, for the defect in host defense. We show in this paper that spontaneous elaboration of active TGF-beta adversely affects host defense against both gram-negative and gram-positive bacterial infection in MRL/lpr mice. Our data indicate that MRL/lpr mice, as compared with congenic MRL/n mice, exhibit decre ased survival in response to bacterial infection, that polymorphonucle ar leukocytes (PMN) from MRl/lpr mice fail to migrate to the site of i nfection during the initial stages of infection, that MRL/lpr mice hav e a significantly increased bacterial burden at the site of infection and at other tissue sites, and that this increased bacterial growth oc curs at a time (>20 h after infection) when PMN influx is greatly enha nced in MRL/lpr mice. Most intriguingly, the alteration in PMN extrava sation during the initial stages of infection and failure to restrict bacterial growth in vivo could be duplicated in MRL/n mice with a pare nteral injection of active TGF-beta 1 at the time of bacterial challen ge. Moreover, these alterations in host defense, including survival in response to lethal infection, could be ameliorated in MRL/lpr mice by the parenteral administration of a monoclonal antibody that neutraliz es the activity of TGF-beta. These data indicate that elaboration of T GF-beta as a result of autoimmune phenomenon suppresses host defense a gainst bacterial infection and that such a mechanism could be responsi ble for the increased risk of bacterial infection observed in patients with autoimmune diseases.