The manufacture of blood plasma products in Scotland: a brief history.

A number of essential clinical products are derived from human blood plasma, including immunoglobulin products for the treatment of infections and disorders of immunity; albumin for protein and fluid replacement and coagulation factors for the treatment of haemophilia and other disorders of haemostasis. For many years, these protein pharmaceuticals were manufactured by the Scottish National Blood Transfusion Service (SNBTS) at its Scottish Protein Fractionation Centre (PFC) in Edinburgh, a contribution which ended with the closure of the PFC in 2008. The origins and development of plasma fractionation in Scotland are summarised in this article, as well as issues which contributed to the closure of the PFC.

The meandering 45-year odyssey of a clinical immunologist.

My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection.

A history of immune globulin therapy, from the Harvard crash program to monoclonal antibodies.

Processes for the large-scale fractionation of human plasma using cold ethanol were initially developed by Edwin Cohn and his colleagues at Harvard to provide albumin as a treatment for shock in World War II. Procedures for further purification of gamma globulins and other proteins precipitating at lower concentrations of ethanol were then developed by Oncley et al. Gamma globulin rapidly replaced convalescent and animal sera for the prevention and treatment of infectious diseases such as measles, hepatitis, and polio, then came into widespread use as replacement therapy in the primary immune deficiencies, which emerged in the antibiotic era of the early 1950s. Although it took 40 years to develop preparations of gamma globulin that could be safely given intravenously, the eventual accomplishment of that goal has led to better treatment of antibody deficiency syndromes and also the wide use of high-dose intravenous immunoglobulin in autoimmune and inflammatory diseases. Those uses continue to expand even as monoclonal antibodies are being introduced for specific infectious diseases in high-risk populations.

Inmunomodulación con inmunoglobulinas endovenosas / Immunomodulation with intravenous immunoglobulins

Las inmunoglobulinas (lgs) disponibles para uso intramuscular han sido usadas en los últimos 40 años como reemplazo en pacientes con déficit primario de células B. Luego del padecimientos de procesos infecciosos específicos, se obtuvieron preparados de lgs, para ser utilizados en profilaxis, a partir de plasma hiperinmune o no seleccionado de donantes. La limitación del uso intramuscular reside en el escaso volúmen de inyección permitiendo sólo la administración 80-100 mg/kg. La producción de lgs para infusión endovenosa (lgEv) a dejado de lado esa limitación y ha permitido tratamientos y estudios con dosis que oscilan entre 0.3 a 2 gramos/kg para una variedad de enfermedades inmunológicas e infecciosas. (AU)

The T-cell receptor as immunoglobulin: paradigm regained.

The quest to determine the molecular nature of T-lymphocyte receptors for antigen was a "holy grail" to immunologists for over 25 years. This paper updates a review written 15 years ago (Marchalonis JJ, Hunt JC. Proc Soc Exp Biol Med 171:127-145, 1982), which proposed that "these molecules apparently do not bear determinants specified by the major histocompatibility complex, but express Ig-related variable regions and constant regions unique to T-cell products." We review subsequent contributions from molecular biology, protein chemistry, peptide immunochemistry, and structural biology establishing that T-cell receptors (TCRs) are members of the immunoglobulin family restricted to T cells that share 3-dimensional structural features, sequence homology, antigenic cross-reactivity, and common mechanisms of diversification with conventional immunoglobulins. These molecules and their light- and heavy-chain siblings appeared contemporaneously in vertebrate evolution with the emergence of sharks. We illustrate how extrapolation of concepts from immunoglobulin to T-cell receptors has aided in the understanding of these often enigmatic molecules, and, conversely, how concepts derived for T-cell receptors such as the role of "superantigens" can be directly applied to conventional immunoglobulins. A second precept that follows from the symmetry of the combining sites of Igs and TCRs is that MHC-restricted antibodies should exist. Such molecules have in fact been reported, and the x-ray crystallography for T-cell receptors suggests that the combining sites recognizing simultaneously MHC and peptide epitopes resemble the combining sites of antibodies directed against protein determinants. Additional immunoglobulin molecules of nonmammalian species have been detected and characterized based upon conserved homology to TCR and Igs, and it is anticipated that further study will enable the identification of more antigen-specific members of the family in mammals as well.

A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature.

On the 30th anniversary of the discovery of IgE, the last immunoglobulin identified, the discovery and subsequent naming of the immunoglobulins is recounted. The first immunoglobulin-like protein to be discovered was the Bence Jones protein or light chain in 1845. Over 100 years, later, the final isotype, IgE, was discovered. During this century, there have been various names for what we now know as IgA, IgD, IgE, IgG and IgM. There was also confusion over what constituted a "new' immunoglobulin and how it should be named. As a result the current nomenclature seems arbitrary; however, it reflects both a historical tradition of preserving the original name of the protein as well as a rational system designed in the early 1960s to codify the basic proteins of the humoral response.