The alternative pathway of T cell activation: biology, pathophysiology, and perspectives for immunopharmacology.

The application of monoclonal antibodies and recombinant mediators to studies of T cell activation has led to a new concept regarding the central mechanisms underlying specific immune responses in man. Stimulation of human T cells to express their functional programs with regard to immunoregulatory activities and effector functions can be mediated through several distinct mechanisms or pathways. We report on the recently discovered T3-Ti antigen receptor independent mode of human T cell activation, namely, the T11-mediated "alternative pathway." Recent evidence supports the notion that this pathway plays an important role in the immune response in man and that failure to activate T cells through T11 is associated with immunodeficiency. The characterization of functional epitopes of the T11 molecule along with functional investigations on patients suffering from etiologically different cases of immunodeficiency provides important perspectives for future pharmacological interventions into the human immune system. It seems likely that immunologic disorders such as autoimmune disease and immunodeficiencies result from overamplification or blockades of the "alternative pathway of T cell activation" and that the T11 epitope represents a potential site for selective inhibition of the "alternative pathway of T cell activation," e.g., by means of synthetic peptide analogues. Conversely, high affinity ligands to the T11 epitope might be suitable for immunostimulation immunodeficiencies that result from circulating blocking factors of the LFA-3/T11 interaction.

Evaluation of phagocytic function in Mycobacterium lepraemurium infection.

Infection of mice with Mycobacterium lepraemurium caused significant functional alterations of the mononuclear phagocyte system. Accelerated clearance of sheep red blood cells was consistently demonstrated throughout the infection and the infected mice showed progressive anaemia. Infected mice showed an enhanced ability to limit growth of phagocytosed Listeria monocytogenes in spleens during the early stages of infection, whereas moribund leprous mice lost this ability. Autoradiography showed that uninfected Kupffer cells and splenic macrophages of moribund mice could still phagocytose Listeria, suggesting that MLM infection did not affect the capacity of Listeria to localize to macrophages but interfered in some way with subsequent killing of such bacteria. The possible mechanisms underlying these observations are discussed.

Symposium on the immunodiagnosis of rheumatic and related diseases, Part II. Rheumatoid factors.

Human rheumatoid factors are antibodies of IgG, IgA, or IgM class that show reactions with antigenic determinants present on other immunoglobulin molecules. The most commonly measured rheumatoid factor relates to the 19S IgM type, which reacts by agglutination of latex particles coated with 7S IgG and is often measured in the standard latex fixation test. Approximately 65 to 70 per cent of patients with rheumatoid arthritis show positive serologic tests for rheumatoid factor; however, a number of other chronic disease conditions are also associated with positive rheumatoid factor reactions, including infective endocarditis, sarcoidosis, leprosy, and other hyperglobulinemic conditions. Although extensive serologic and immunochemical studies have identified a number of specific antigenic structural sites on immunoglobulin molecules that react with rheumatoid factors, recent studies have shown that a certain proportion of such antibodies may show cross-reactivity with DNA-histone complexes as well. It is still not entirely clear how rheumatoid factors fit into the pathogenesis of rheumatoid arthritis itself.

Evaluation of the immune response in mice infected with Mycobacterium marinum.

Foot pad infection of mice with Mycobacterium marinum carried out with a view to comparing the immune response on the humoral level of such mice, with that observed previously in mice infected with M. leprae, indicated that there was a similarity in terms of the first appearance and proliferation of immunocytes and the time at which the peak and decline in the antibody-producing cells occurred. The significant difference appeared to be in the immunoglobulin G response, which was absent in the M. leprae infected mice, but occurred simultaneously with the immunoglobulin M response at a high level, both during a primary and after a secondary challenge administered 15 days post-primary infection in the M. marinum infected mice. Further confirmation was obtained through additional studies on the specific immunoglobulin levels and determination of both immunoglobulin M and immunoglobulin G antibodies by hemagglutination. Although the growth temperature requirement of the two organisms and their ability to initiate infection in areas of the body with lower temperatures are similar, it is suggested that the type of infection induced by each one of these species in the mouse may disallow the serious consideration of the M. marinum infection model as a possible alternative experimental model for studying the role of host immunity to M. leprae infections in mice.

Immune response to Mycobacterium leprae: plaque-forming cells in mice.

Intravenous immunization with a cell extract of Mycobacterium leprae produced a primary immune response of considerable magnitude, followed by an equally large response after secondary stimulation, as measured by assay of plaque-forming cells (PFC). Infection with M. leprae or immunization with cell extract by the footpad route produced a lower level of response than that seen in the intravenous group. Identical patterns of response, although not of the same magnitude, were observed after both primary and secondary challenges in the two footpad groups, one infected with viable M. leprae and the other immunized with M. leprae cell extract. The secondary response after a booster dose to all these groups appeared to be an enhanced immunoglobulin M response. Control studies confirmed that the immune response was a direct result of the host-parasite interaction and that the PFC observed resulted from stimulation of antibody-forming cells by antigens of M. leprae. The similarity in time of appearance of peak PFC levels in the two footpad groups may be attributed to the live challenge passing through a latent phase. Alternatively, the challenge is known to contain a large proportion on nonviable cells, and it may also contain soluble M. leprae antigens. Studies of the cross-reactivity of the antigens have extended previous observations on antigens shared between M. leprae and other mycobacterial species. Use of the two antigen-containing fractions of the M. leprae cell extract has suggested that one of the fractions contains some shared antigens, whereas the other has an antigen specific to M. leprae.

A study of clofazimine in the rat.

1. Clofazimine, an anti-mycobacterial agent used in the treatment of leprosy, has been reported to be particularly effective in the treatment of acute erythema nodosum leprosum reactions.2. The present experiments were designed to study in the rat this apparent anti-inflammatory activity.3. In doses relatively non-toxic to the animals clofazimine inhibited both rat adjuvant arthritis and the inflammatory paw swelling following an adjuvant injection.4. Clofamizine failed to inhibit both the primary antibody response to sheep erythrocytes and the tuberculin skin response.5. It is concluded that clofazimine exhibits definite anti-inflammatory (but not immunosuppressive) activity, and that it should be tested in patients with rheumatoid arthritis.