The antigenic stimulus

The work presented in this thesis is submitted as a contribution to the understanding of the physiology of the immune response. It is primarily concerned with the initiation of the reaction to the stimulus of antigen and examines particularly how immunological adjuvants might promote this reaction. Chapter 1 Introduction The relevant literature on the nature of antigenicity and antigen processing is discussed against the background of the various theories of the mechanisms of the immune response. The localization of antigen in lymphoid tissues is regarded as a starting point for the investigation of the events related to antigenic stimulation. Chapter 2 The Immune Response in the Chicken to a Soluble Protein Antigen The first study provides a re-examination of the immune response in the chicken using antigen labelled with radio-isotopes. The elimination of antigen, the appearance and removal of circulating antigen-antibody complexes, and the production of circulating antibody are examined and correlated with the localization of antigen in the spleen as observed by autoradiography. The cellular events in the spleen are discussed along with the complementary findings obtained with the fluorescent antibody technique by my colleagues (White, French and Stark, 1967 - Appendix B to the thesis). Chapter 3 Immunological Adjuvants and their Modes of Action The physical and pharmacological effects of various immunological adjuvants are outlined and their ability to affect the immunological mechanism discussed. Chapter 4 Observation of Adjuvant Action The action of classical adjuvants was observed in a model in which a poor antigen, bovine 7-globuline (BGG) normally unable to stimulate a response in the strain of mouse used, is able to do so because of the adjuvant. The immune response is recognized by the elimination pattern of the antigen as measured by whole-body counting of individual mice. It was found that the adjuvant substances increased the rate of protein katabolism in addition to producing the immune response. Further experiments were therefore undertaken to see if increasing the rate of protein katabolism alone affected the antigenicity of the NGG. Observations were also made to determine whether slowing of the katabolic rata affected the performance of adjuvants. It was found that increased katabolism as brought about by thyroid hormone set up a latent immunization which was detectable on a secondary exposure to antigen. Slowing the katabolism by an altered diet or environmental temperature had a slight depressant effect on antibody production. Chapter 5 Handling of Injected Materials The kinetics of handling of indigestible and digestible materials is considered. An analogy is drawn between the control of immunoglobulin katabolims in some species (as observed experimentally by others) and the disposal of antigen within an immunologically competent cell in that in both cases there might be competition for specific receptors within digestive vesicles. The suggestion is further made that antigen fragments are able to penetrate the vesicular membrane if they are received onto the specific receptor and having done so can then induce specific cellular differentiation. This hypothesis would predict that agents non-specifically increasing the permeability of the membrane would have an adjacent action. Chapter 6 The Relationship of Membrane Permeability to Antigenic Stimulation Vitamin A, an agent known to increase membrane permeability in another context is used in three experimental models to determine whether it has adjuvant activity. Evidence of adjuvant activity in the production of humoral antibody in the mouse is obtained but the vitamin has not been demonstrated to bring about delayed-type hypersensitivity to a purified protein antigen in the guinea pig. The significance of these findings is discussed. Chapter 7 Conclusion The experimental findings and their implications are further discussed