Immunology. Supplement最新文献

The observation that the local site of autoimmune responses over-expressed HLA class II led to the formulation that tissue antigen-presenting capacity contributes significantly to the mechanism of autoimmune disease perpetuation, by continually reactivating auto-antigen-reactive T lymphocytes. These in turn produce mediator molecules which maintain HLA class II expression (and hence antigen-presenting capacity) in the target tissues; and also initiate the immune and inflammatory pathways. The importance of this concept is that it provides a readily testable hypothesis that has been investigated extensively. For the thyroid diseases compelling data to support it have accumulated; in other diseases such as rheumatoid arthritis the evidence is increasing. The concept also relates the human autoimmune diseases to the normal mechanisms of immune induction and immunoregulation. This highlights the areas that we do not yet understand, namely the interplay of genetic susceptibility, extrinsic agents or disorders of immune regulation which permit the autoimmune process to become sufficiently pronounced as to engender a clinical autoimmune disease. Even with our limited understanding of the disease process, it is apparent that there are many opportunities for newer approaches at therapy, based on interfering with the immune cells or their mediators.

Leprosy is of interest to immunologists because the varied clinical manifestations of the disease correlate closely with the immunological spectrum. Resistance to infection is dependent on appropriate cell-mediated immunity, but patients with the lepromatous form fail to respond to antigens of M. leprae. In vitro studies have revealed the existence of T-suppressor cells of the phenotype CD8+, CD3+, HLA-DR+, FcR+, 9.3-, which are restricted by major histocompatibility complex (MHC) class II antigens. Several new candidate vaccines against leprosy have been effective in breaking immunological unresponsiveness and engendering cell-mediated immunity in lepromatous leprosy patients, including the combination of BCG+ killed M. leprae. Because BCG has unique adjuvant properties, we have begun to use molecular genetic approaches to develop BCG into a multivaccine vehicle capable of immunizing simultaneously against several pathogens. Both phage-based and plasmid-based strategies have been successfully developed for introducing selectable markers into BCG for the first time.

Using a newly developed FACS method for quantifying the expression of the Escherischia coli lacZ reporter gene in viable mammalian cells, we have obtained cloned cell lines in which the expression of lacZ is under the control of native endogenous transcription elements. We infected the murine pre-B cell 70Z/3 with transcriptionally disabled retroviruses containing lacZ and employed the FACS-FDG technique to detect and sort rare lacZ+ cells in which we expect integration is near such endogenous transcription elements. After two rounds of enrichment we obtained a population of cells that was 80-90% positive for lacZ activity. Clones derived from the lacZ+ pool differ from each other with respect to their overall level of lacZ activity as well as in the pattern of lacZ expression among cells within an individual clone. Treatment of these lacZ+ 70Z/3 clones with lipopolysaccharide (LPS; which is known to stimulate differentiation of 70Z/3 from a pre-B cell to an IgM-expressing B cell) greatly decreased lacZ expression in one clone, 7e17. lacZ expression in this clone was 50-100 times lower within 24 hr of LPS addition and coincided with the acquisition of IgM kappa on the surface of 7e17. This suggests that a transcriptionally active domain of chromatin that harbors the lacZ construct is down-regulated during the transition induced by LPS stimulation.

As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone.

I-J has been found to be an inducible isomorphic molecule expressed on class II-restricted T cells. It undergoes a systematic adaptive change in radiation bone marrow chimeras according to the environmental major histocompatibility complex (MHC). Recent biochemical studies demonstrated that I-J is a homodimer of MW 84,000-90,000 composed of 42,000-46,000 MW glycopeptide subunits. The molecule is different from class II-restricted T-cell receptor, class II antigens or putative mouse CD28. The ligation of I-J molecules with anti-I-J results in the suppression of T-cell responses by the inhibition of early signal transduction through antigen recognition.

The papovavirus SV40 is able to induce tumours in susceptible hosts and will transform cells in vitro. Its major early protein, large T antigen, is required for viral DNA synthesis, both in vivo and in vitro, and is also responsible for the oncogenic action of the virus. We have made use of an extensive library of anti-T monoclonal antibodies to investigate the cellular effects of T. Large T shares an antigenic determinant with a growth-regulated host protein, p68, which is a member of an expanding super-family of helicases with particular homology to the translation initiation factor elF-4A. We have also studied the binding and interaction of large T with two particular host components: the replicative enzyme DNA polymerase alpha and the proto-oncogene p53. These two proteins bind to similar regions of T and exert similar effects on its antigenic structure. We found that p53 can block the binding of DNA polymerase alpha to T as well as co-existing with DNA polymerase alpha in a trimeric complex with T. This suggests that these interactions may be important in the oncogenic and replicative action of large T.

Birth control vaccines constitute a new category of vaccines. Immunization with the objective of selectively blocking a physiological process differs in many respects from immunizing against pathogens. Conceptually, these widen the orbit of therapeutic intervention by immunological methods. Success recorded in making vaccines regulating fertility offers models to regulate any other physiological process in the body. At a practical level, the task of making such vaccines is beset with inherent difficulties and with new challenges. This article, dedicated to Avrion Mitchison, aims to discuss these problems and to record successes wherever achieved.