Protective autoimmunity is a physiological response to CNS trauma.

Primary damage caused by injury to the CNS is often followed by delayed degeneration of initially spared neurons. Studies in our laboratory have shown that active or passive immunization with CNS myelin-associated self-antigens can reduce this secondary loss. Here we show, using four experimental paradigms in rodents, that CNS trauma spontaneously evokes a beneficial T cell-dependent immune response, which reduces neuronal loss. (1) Survival of retinal ganglion cells in rats was significantly higher when optic nerve injury was preceded by an unrelated CNS (spinal cord) injury. (2) Locomotor activity of rat hindlimbs (measured in an open field using a locomotor rating scale) after contusive injury of the spinal cord (T8) was significantly better (by three to four score grades) after passive transfer of myelin basic protein (MBP)-activated splenocytes derived from spinally injured rats than in untreated injured control rats or rats similarly treated with splenocytes from naive animals or with splenocytes from spinally injured rats activated ex vivo with ovalbumin or without any ex vivo activation. (3) Neuronal survival after optic nerve injury was 40% lower in adult rats devoid of mature T cells (caused by thymectomy at birth) than in normal rats. (4) Retinal ganglion cell survival after optic nerve injury was higher (119 +/- 3.7%) in transgenic mice overexpressing a T cell receptor (TcR) for MBP and lower (85 +/- 1.3%) in mice overexpressing a T cell receptor for the non-self antigen ovalbumin than in matched wild types. Taken together, the results imply that CNS injury evokes a T cell-dependent neuroprotective response.

Delivery of cytokines by liposomes. III. Liposome-encapsulated GM-CSF and TNF-alpha show improved pharmacokinetics and biological activity and reduced toxicity in mice.

In an attempt to potentiate the therapeutic index of cytokines, recombinant mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) and recombinant human tumor necrosis factor alpha (TNF-alpha) were encapsulated in large (0.3-2.2 microns) multilamellar vesicles composed of various lipids, using several encapsulation methods. Liposomal cytokine activity was tested in vitro and in vivo and was compared with that of the soluble cytokines. The main observations were as follows: (a) The mean encapsulation efficiency, as determined by bioassays, was 49-79%, depending on the formulation, for GM-CSF, and 48% for TNF-alpha; (b) some of the entrapped cytokine preparations displayed high stability at 4 degrees C, with < 30% loss of biologic activity during a 4-month period; (c) release of TNF-alpha, but not of GM-CSF, from the liposomes was required for their biological activity in vitro; (d) plasma half-lives (t1/2 alpha, t1/2 beta) and the area under the curve (AUC) of the entrapped cytokines were 10-20 times greater than those of the soluble cytokines; (e) the toxicity of liposomal TNF-alpha was one-third and one-seventh that of soluble TNF-alpha in normal and tumor-bearing mice, respectively; (f) administration of liposomal GM-CSF (5 x 10(4)-2 x 10(5) U, one to five times) to normal and 5-fluorouracil-treated mice led to a two- to fourfold increase in the absolute number of peritoneal and spleen leukocytes and of GM colony-forming cells in the spleen, as compared with the levels obtained using soluble GM-CSF; and (g) under the experimental conditions used, neither free nor liposomal GM-CSF significantly increased the absolute number of blood leukocytes, although liposomal GM-CSF markedly (threefold) enhanced the level of blood granulocytes. Collectively, these findings suggest that liposome-entrapped GM-CSF and TNF-alpha may be more efficacious immunomodulators than the soluble cytokines.