Effective supernatants (SUP), which potentiate mouse T-cell responses to phytohemagglutin (PHA), are obtained from cells of several species (human, rabbit, rat, mouse) and indeed from syngeneic spleen, thymus, or bone marrow cells. Unstimulated cells release some SUP activity but more is produced after stimulation. Lipopolysaccharide (LPS) produced very active SUP in all cultures tested. PHA was similarly active on human leukocytes only, whereas concanavalin A (Con A) gave highly efficient SUP only with mouse spleen cells. SUP production is not correlated with a mitotic response of the donor cells and is observed in cultures unable to respond mitotically to the stimulant. Adherent mouse spleen cell populations, consisting largely or entirely of macrophages, produce active SUP, while nonadherent cells do not. Similarly, purification of human peripheral leukocytes on nylon columns, with removal of macrophages and other adherent cells, destroys their ability to produce SUP. The importance of indirect effects in stimulating mitotic responses of T cells is emphasized by the fact that the mitotic response of mouse thymocytes to LPS and its ability to potentiate the response of these cells to PHA disappears with removal of adherent cells from the thymocyte population. Conversely the production of SUP from spleen cells stimulated by Con A requires the presence of T cells.

Human and mouse lymphoid cells, stimulated by phytohemagglutinin (PHA) or lipopolysaccharide W (LPS), release supernatant factor(s) which are mitogenic for mouse thymocytes and which potentiate their responses to PHA or concanavalin A (Con A), The term LAF (lymphocyte-activating factor) is proposed for this activity. LAF not only enhances the mitotic responses of the less dense thymus subpopulations (A, B, and C) separable on discontinuous bovine serum albumin (BSA) gradients but also gives substantial responses in the otherwise inert cells of the denser fractions D and P. LAF does not exert a potentiating stimulatory effect on the responses of unfractionated mouse spleen cells, but does act synergistically with PHA on nonadherent spleen cells and on spleen cells of mice of several strains 5 days after irradiation and injection of thymocytes. Similarly LAF, which has no visible effect on unfractionated human peripheral blood cells, strongly potentiates the PHA response of column-purified lymphocytes, when these are cultured at low concentration. We conclude that LAF stimulates both central and peripheral T lymphocytes and enhances their responses to other stimulants.

In experimental allergic encephalomyelitis (EAE), produced by injecting rabbits with whole rabbit spinal cord together with tubercle bacilli and mineral oil, lesions comparable to those seen in the central nervous system are found in the nerve roots, spinal ganglia, and peripheral nerves. When special fractions of bovine white matter are used as antigen in rabbits, the same distribution of lesions is seen but peripheral nerve involvement is relatively less frequent. When rabbit sciatic nerve or spinal ganglia are used as antigen in rabbits, lesions occur only in the roots, ganglia, and peripheral nerves. Lesions are not produced in the central nervous system, nor is there a meningitis. This disease picture has been called experimental allergic neuritis (EAN). The antigenicity of rabbit nerve is not impaired by autoclaving. Sciatic nerve of other mammalian species produces the same disease in rabbits as does rabbit nerve. Optic nerve, used as antigen, produces the typical picture of EAE, not EAN. The optic nerves are not affected in EAN, whereas they commonly contain lesions in EAE. There are differences of symptomatology, referable to the difference in distribution of lesions, between EAE and EAN. The spinal fluid of EAE shows an increase both in the number of cells and in the total protein content. In EAN, the same changes in protein are observed, but usually the cell count remains normal. The cell count appears to be related to the involvement of cerebral and spinal meninges, which is an almost invariable accompaniment of EAE. The skin tests and serologic studies made with homologous and heterologous antigens were essentially non-contributory, apparently as a consequence of the diversity of antigens present in the inoculated materials. The similarity between EAN and certain of the human polyneuritides is indicated and discussed.

A generalized disease is induced experimentally in the rat by administration of Freund's adjuvant. The primary clinical and pathologic lesions are arthritis, periarthritis, peritendinitis, and periostitis in the joints of the extremities and tail. Accompanying the arthritis in some cases, and never observed in its absence, are other specific tissue lesions including iridocyclitis, nodular lesions in the glabrous skin (ear, genitalia, feet, tail), transient rashes, a chronic skin disease, genitourinary lesions, and diarrhea. These make up a striking and characteristic picture. The arthritis usually precedes the other lesions and, together with the skin disease may show a prolonged and fluctuating course. Visceral lesions do not occur. Histologically, the basic lesion is a lymphocytic and histiocytic infiltration, initially perivascular and subsequently more disseminated. In addition, in the region of the joints and in the corpora cavernosa of the penis, there is extensive proliferation of mesenchymal cells, especially fibroblasts. Foci of fibrinoid necrosis are seen in the articular and nodular lesions, and destructive lesions of the joints are common. Such a combination of tissue lesions has not previously been described in experimental pathology. The experimental disease is shown to have both similarities to and differences from Reiter's syndrome, rheumatoid arthritis, and certain other disorders which occur in man.