Pathologic mechanism of pulmonary graft rejection.

necrosis, and abscesses. The systemic effects include disseminated intravascular coagulation. Increased levels of TNF in humans would likely result in similar alterations. The importance of TNF in human diseases was first reported in patients with gram-negative sepsis (purpura fulminans of meningococcemia). Also, it has a pathogenetic role in cerebral malaria, both human and experimentally induced. In both of these life-threatening conditions, elevated blood TNF levels on admission have correlated with an increased incidence of death or sequelae. Based on experimental data, the use of anti-TNF antibodies is promising as a therapeutic tool. Clinical trials of monoclonal antibody are underway in patients with gram-negative septic shock, cerebral malaria, and the OKT3-induced syndrome (in the context of transplantation). Other conditions associated with alterations of TNF in humans include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, cystic fibrosis, graft-versushost disease, sarcoidosis, some parasitic infections (aside from malaria), septic arthritis, leprosy, and the acquired immunodeficiency syndrome. Patients with chronic heart disease have high serum levels of TNF, especially if they are cachectic. Such elevations in cachectic patients may be associated with activation of the renin-angiotensin system. In some conditions where blood TNF alterations are not detectable, dramatic changes may be found in other body fluids, such as in bronchial aspirates of patients with the adult respiratory distress syndrome. It appears that some neoplasms, including a human breast carcinoma and a mouse fibrosarcoma, secrete TNF in vitro. There is even a transplantable mouse tumor line genetically altered to continuously secrete human TNF. Thus, the possibility of using levels of blood TNF as markers of neoplastic activity has been raised. Some investigators have found TNF immunoreactivity in the serum of50% of patients with ovarian, breast, and colon carcinoma, lymphomas, and myeloma; in 18% of patients in complete remission; and in 3% of normal subjects. Other investigators have not detected TNF in cancer patients. Discrepant results of some TNF assays could be explained by the presence ofTNF inhibitors, which would inhibit bioactivity but not immunoreactivity. Although the name "tumor necrosis factor" was derived from the observation that it produced lysis ofa murine tumor, subsequent research on its putative antineoplastic effects has been generally disappointing, especially for human tumors. It is cytotoxic for some animal (such as L929 fibroblasts) and human tumor cell lines and does cause necrosis of some experimental neoplasms, but it seems to be ineffective in vivo against a good many human tumors, and toxicity is often reached before tumoricidal effect. Nevertheless, clinical trials with recombinant TNF are in progress. It is possible that the addition of other cytokines, or conventional chemotherapy, radiotherapy, or hyperthermia may potentiate the antineoplastic effects of tolerable doses of TNF.