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Altered macrophage function after thermal injury is associated with increased production of PGE2 and TNF. However, it is not clear why synthesis of both cellular products remains elevated, as PGE2 is a potent inhibitor of TNF secretion. We studied the relationship between PGE2 and TNF synthesis in a murine model of thermal injury, and examined the effect of prostaglandin blockade on splenic macrophage secretion of these mediators of inflammation. LPS-stimulated production of PGE2 was significantly elevated in burn groups compared with sham-burned controls (pg/ml mean(SEM); sham 151(32): burn 597(147), p0.01). TNF production was similarly increased after thermal injury (pg/ml mean(SEM); sham 62(20): burn 928(316), p0.01). In vitro culture of macrophages with indomethacin augmented LPS stimulated TNF production in sham-burned controls but did not affect synthesis in burn groups, suggesting a loss of PGE2-dependent regulation of TNF synthesis after thermal injury. Direct measurement of TNF secretion as a function of exogenous PGE2 confirmed this dissociation between PGE2 and TNF synthesis, as burned animals displayed a 5-fold reduction in sensitivity to PGE2-induced inhibition of TNF, when compared with sham-burned controls (ID50 PGE2 molar; sham 1.26 x 10(-8): burn 6.43 x 10(-8), p0.05). In vivo pretreatment of burn groups with indomethacin for 5 days before assay partially restored sensitivity to the prostaglandin, and significantly down-regulated synthesis of both TNF and PGE2. These data show that thermal injury is associated with a loss of PGE2-dependent down-regulation of TNF synthesis, which accounts at least in part for increased TNF in these animals. In vivo cyclooxygenase blockade partially restored sensitivity to the prostaglandin and consequently down-regulated synthesis of TNF. These data further support existing evidence that suggests a potential therapeutic role for cyclooxygenase blockade after major thermal injury and trauma.

An immunosuppressive peptide fraction was isolated by means of gel filtration, membrane partition, and ion-exchange chromatography from the sera of patients hospitalized for cancer. The resulting peptide fraction, which was heterogeneous as judged by high-voltage electrophoresis, was found to suppress both phytohemagglutinin-induced proliferation of lymphocytes in vitro and the in vivo induction of splenic plaque-forming cells in mice. The specific activity of the peptide fraction, which was isolated from the sera of cancer patients, was significantly increased over that of the unfractionated starting material. Moreover, in control experiments, when the sera of normals or non-cancer-bearing hospitalized individuals were subjected to the same chromatographic techniques, no active peptide fraction could be obtained.

Impaired immune competence leading to decreased resistance to sepsis is a major cause of death in burn patients. We have previously shown that increased mortality from a septic challenge correlated with impaired splenocyte interleukin-2 (IL-2) production and response to T cell mitogens in mice subjected to a 25% surface area scald burn. We report now that the addition of recombinant (r) IL-2 (100 U/ml) in vitro to splenocytes from burned animals restored mitogen responses to normal. Burned mice intraperitoneally received 16,000 U of rIL-2 (selected on the basis of dose-response experiments) once daily in 0.5 ml 5% dextrose (5% D) on days 1 through 6 after thermal injury and were compared with burned mice treated with only 5% D. Both groups were subjected to cecal ligation and puncture 10 days after burn; 4 days later, there were no survivors in the 5% D group, whereas 45% of the rIL-2 group remained alive (p = 0.001; Gehan statistic). We found that rIL-2 treatment at the dose selected resulted in no apparent toxicity in burned mice. Finally, splenocytes from rIL-2-treated burned mice showed improved responses to T cell mitogens in vitro compared with 5% D-treated controls. We conclude that rIL-2 therapy may have a role in the restoration of immune competence after thermal injury.

The alpha-globulin-rich fraction of Cohn Fraction IV, designated IRA, suppresses the in vitro antibody response to sheep red blood cells (SRBC) without cytotoxicity. IRA was effective if added before or up to 24 hr after antigen exposure. The suppression could be reversed after 24-hr treatment by washing the cells two to three times; after 48 hr of IRA treatment, however, suppression could only be partially reversed. The addition of a population of thymus-derived cells educated to the antigen SRBC could effectively reverse the IRA-induced inhibition of antibody production, whereas BSA-educated T cells could not.

Intravenous donor antigen in the form of spleen cells can significantly potentiate the effects of ALS in prolonging the survival of skin allografts exchanged across both weak and strong histocompatibility barriers. This effect depends on the proper timing of antigen administration and can result in immunologic unresponsiveness of sufficient strength to permit acceptance of second set grafts. The skin allograft itself apparently plays a role in the establishment of this unresponsive state since ALS and antigen alone followed by delayed allografts at 21 days resulted in normal graft rejection times.