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G J Nossal

Publications and source records attributed to G J Nossal.

At least 19 recordsLinked to original sources
PubMed1998

WHO and health research--some personal reflections.

WHO's health research effort is reviewed through the eyes of an outside supporter. Drawing on his 30 years of experience with particular WHO programmes and the Advisory Committee on Health Research, the author highlights some of the important changes that have occurred, and his own involvement in bringing them about.

Allergy and Immunology↗
PubMed1997

Host immunobiology and vaccine development.

As the rules of immunoregulation become clearer, the design of vaccines and adjuvants is becoming more scientific. To understand these rules, the interactions between three kinds of cells need to be grasped. Antigen-presenting cells (APCs) initiate the immunoglobulin cascade. The most important of these are dendritic cells, which must first capture antigen, a process aided by particulate matter, the presence of natural or acquired antibodies, or the capacity to activate complement. Then T cells become activated through conjoint action of processed antigenic peptides and APC surface and secreted molecules. T cells mediate inflammation, develop cytotoxic capacity, and help in antibody formation. Whether cells of type 1 or type 2 predominate influences the direction of both cellular and humoral responses. B cells are then activated, leading to antibody formation and often to better antigen presentation. Both T and B cell memory, embedded in long-lived lymphocyte populations, aid heightened immune reactivity when the antigen is re-encountered. The best vaccines stimulate strong memory.

Antibody Formation↗
PubMed1997

The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response.

Immunization with protein-containing antigens results in two types of antigen-specific B cell: antibody forming cells (AFCs) producing antibody of progressively higher affinity and memory lymphocytes capable of producing high affinity antibody upon re-exposure to antigen. The issue of the inter-relationship between affinity maturation of memory B cells and AFCs was addressed through analysis of single, antigen-specific B cells from the memory and AFC compartments during the primary response to a model antigen. Only 65% of splenic memory B cells were found capable of producing high affinity antibody, meaning that low affinity cells persist into this compartment. In contrast, by 28 days after immunization all AFCs produced high affinity antibody. We identified a unique, persistent sub-population of bone marrow AFCs containing few somatic mutations, suggesting they arose early in the response, yet highly enriched for an identical affinity-enhancing amino acid exchange, suggesting strong selection. Our results imply that affinity maturation of a primary immune response occurs by the early selective differentiation of high affinity variants into AFCs which subsequently persist in the bone marrow. In contrast, the memory B-cell population contains few, if any, cells from the early response and is less stringently selected.

Amino Acid Sequence↗
PubMed1997

B lymphocyte physiology: the beginning and the end.

Whereas lymphatic tissues were implicated as the chief sites for antibody production almost 100 years ago, three findings cemented the role of the plasma cell as the actual producer, namely the histological and tissue culture studies of Fagraeus, the beautiful immunofluorescent approach of Coons and his group, and the micromanipulation approach to the study of antibody formation by single cells introduced by Lederberg and myself. Proof that antibody-forming cells derived from B, rather than T, cells had to await the studies of Miller and Mitchell, with some minor technical contributions from myself. The physiology of the germinal centre also has a long history, and recently much interest has surrounded the relative roles of germinal centres as sites of somatic immunoglobulin V gene hypermutation and selection of high affinity B cells, versus the roles of extra-follicular proliferative foci as sources of the primary antibody response. Tolerance and self-antigens within the primary B lymphocyte repertoire is secured by clonal deletion within the bone marrow of those cells which are operationally the most threatening to the body, and a second level of functional impairment of B cell activity and life-span, capable of being induced centrally or peripherally, termed clonal anergy. As these concepts became progressively more refined through transgenic models of immunological tolerance, we turned our attention more towards tolerance within the secondary B lymphocyte repertoire. This is generated primarily inside germinal centres, where it appears that two quite separate mechanisms act as a bulwark against the possible creation of hypermutated anti-self cells. The first is that germinal centre activity and memory cell generation are dependent on antigen-specific, germinal centre-seeking CD4+ T cells, and if a putative anti-self mutant B cell gets no help because of T cell tolerance, it will not expand further. The second is a very specific mechanism confined to the germinal centre whereby antigen-specific B cells are especially sensitive to antigen-induced apoptosis if soluble, deaggregated antigen is presented to them before they reach the 'rescue' signal of follicular dendritic-cell-bound antigen. While some of the death in germinal centres is clearly apoptotic in nature, a further phenomenon observed electron microscopically relates to the formation of type B dark cells. It is not yet clear whether the DNA in this type of dying cell is cleaved. Transgenic expression of bcl-2 in germinal centre B lymphocytes confers incomplete protection from apoptosis caused by soluble antigen. The suggestion that at least some of this apoptosis is mediated via Fas-Fas ligand interactions is prompted by the observation that the apoptotic phenomenon is markedly reduced in lpr mice.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1997

Awakening the global conscience: who will benefit from new vaccines in the 21st century?

The World Health Organization's (WHO) Global Programme for Vaccines and Immunization has three linked aims. The first is to give the so-called Expanded Programme on Immunization (EPI) vaccines to as many of the 125 million children who are born into the world each year as possible. The second is to ensure for the world an adequate supply of vaccines, and to safeguard vaccine quality. The third is in the field of vaccine research and development, not only coordinating the worldwide effort for new and improved vaccines but also preparing the way for their introduction into the EPI and continually to seek ways to simplify vaccination schedules. Enormous effort has gone into the polio eradication campaign. Following brilliant progress in both India and Africa, the goal of eradication by the year 2000 or shortly thereafter now seems achievable. Although a decision has not yet been taken, an attempt at measles eradication may well be the next huge challenge. The Global Programme for Vaccines and Immunization (GPV) is closely tied up with the Children's Vaccine Initiative (CVI) which is the name given to an umbrella organization which seeks to unite all the forces in the world promoting widespread use of vaccines. The chief functions of CVI are to be a strategic think tank, particularly as regards priorities; and to be a strong, consistent and effective advocacy group. Previously there had been some misunderstanding of the respective roles of WHO and CVI. These have now been cleared up by a dual stratagem--one single person, Dr JW Lee, as the administrative head of both Programmes; and one single Scientific Advisory Group of Experts or SAGE to guide the scientific aspects of both Programmes. The author has the honour of being Chairman of SAGE. It is apparent, however, that resource constraints are looming large in the affairs of both GPV and CVI. Clearly, the newer vaccines will be more expensive than the traditional ones, and the world must grope for new mechanisms to bring the fruits of the current upsurge of interest in vaccine development to all the countries of the world, not just the affluent ones.

Developing Countries↗
PubMed1996

The xid mutation diminishes memory B cell generation but does not affect somatic hypermutation and selection.

In this study, we examine the relationship between primary and secondary T cell-dependent immune responses using the response of xid mice to the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) as an experimental model. The reduced serologic primary immune response of xid mice was demonstrated to be caused by a substantially decreased Ab-forming cell (AFC) generation. Furthermore, the germinal center reaction in the primary xid immune response was diminished and the frequency of NP-specific memory B cells prior to secondary immunization was reduced 10-fold. Despite the poor primary response of xid mice, secondary exposure to Ag generated a response that was qualitatively and quantitatively equal to that of wt mice. The number of IgG1 AFCs in spleen and bone marrow increased equally in both groups, as did the proportion of AFCs secreting high affinity Ab in both locations. The extent and distribution of somatic mutations in the V(H) genes of xid secondary response B cells was also found to be normal, indicating that the xid gene product is not critical for the processes that result in affinity maturation. Thus, although xid mice generate memory B cells of normal phenotype but at a substantially lower frequency, this does not limit the magnitude of the secondary response. Therefore, our results imply that the reduced memory B cell frequency in xid mice is still above some threshold value necessary for a normal secondary immune response.

Animals↗
PubMed1996

The phenotype and fate of the antibody-forming cells of the splenic foci.

The first product of the humoral response to antigen is low-affinity antibody, produced by extrafollicular foci of antibody-forming cells (AFC) in organs such as spleen and lymph node. These cells proliferate rapidly but then undergo an equally rapid decline, so that they are present in only small numbers 14 days after immunization. We have used 6-parameter flow cytometry to isolate and examine the characteristics of (4-hydroxy-5-nitrophenyl)acetyl-specific AFC, looking in particular for those markers that might differentiate them from cells of the intrafollicular (germinal center) arm of the T-dependent immune response. At day 7 of the primary response, most AFC were found to express surprisingly low levels of B220, high levels of syndecan, and retain significant levels of surface IgG1. We then used enzyme-linked immunospot assays to demonstrate that the rapid decline of these cells was not likely to be due to migration to organs such as the bone marrow. Their decline could, however, be explained by apoptosis in situ, which was demonstrated immunohistologically by nick-end labeling.

Animals↗