Immunoglobulin use in immune deficiency and autoimmune disease states.

Although immunoglobulin (Ig) has been available since the 1950s for replacement therapy in primary immune deficiency, many other effective uses of this class of biologics have been investigated and evolved over recent decades. Ig administration has become common practice in the treatment of the immunocompromised patient and has recently expanded into the treatment of those patients with an inflammatory disease and autoimmune neuropathies per established clinical guidelines. As research into the genetic basis of disease advances, clinicians should better assess complex data surrounding safe and effective uses of Ig to treat patients who present with B-cell and T-cell deficiencies, along with those harboring gene deletions or genetic anomalies who may potentially benefit from Ig therapy. Evidence-based clinical indications for the use of Ig include idiopathic thrombocytopenic purpura, B-cell chronic lymphocytic leukemia, Kawasaki disease, chronic idiopathic demyelinating polyneuropathy, multifocal motor neuropathy, bone marrow transplantation, and pediatric HIV infection, among others, and have evolved over time. Ig is also often tried in refractory cases that might benefit from its anti-inflammatory effects or empirically in off-label situations. Due to its anti-inflammatory effects, high-dose Ig has been used for numerous off-label indications with varying levels of effectiveness and evidence to support its use. A review of all autoimmune conditions for which Ig has been used is beyond the scope of this article and newer treatments are available for many of these disorders. Here the focus will be on selected conditions in which Ig has clear benefit. Because there is a limited supply of Ig and a need for further research into optimal use, it is important for healthcare professionals to better understand current and developing indications and data/levels of evidence to support Ig therapy as its role continues to evolve.

Subcutaneous immunoglobulin replacement therapy: the European experience.

PURPOSE OF REVIEW: Rapid subcutaneous immunoglobulin (SCIg) infusions have been used as an important method of delivering replacement immunoglobulin (Ig) to patients with primary immune deficiencies (PIDs) in Europe over the last 25 years. This review provides a comprehensive interpretation of the literature relating to the administration of SCIg and the services that have been developed alongside. RECENT FINDINGS: Using rates of at least 20 ml/h per infusion site and simultaneous sites, the infusion time once per week is short (1-2 h in adults) and using small portable pumps, the child or adult is free for other activities during the therapy. The rapid SCIg infusions have been documented as well tolerated, efficacious and acceptable to infants and their parents, children, adults and elderly patients, and more recently to patients with autoimmunity requiring immunomodulatory Ig doses. SUMMARY: As part of PID diagnostic and management services, educational programmes for self-infusion of both intravenous Ig and SCIg at home have been developed throughout Europe, resulting in increased patient compliance and patient empowerment as well as cost-savings for healthcare providers.

History of primary immunodeficiency diseases.

PURPOSE OF REVIEW: This issue of Current Opinion in Allergy and Clinical Immunology is focused on primary immunodeficiency diseases (PIDs). Like every disorder, PID has its own specific history, starting with the discovery of agammaglobulinemia in 1952 and still expanding at a rapid pace, covering, at the time of this publication, more than 180 genetically determined disorders. However, as this report attempts to demonstrate, the history of PID is intertwined with the development of modern medicine and is the direct result of the innovative thinking of physician scientists who introduced new concepts in pathology, microbiology, biochemistry, and immunology, based on carefully designed experiments. As a consequence of the novel ideas put forth in the late 19th century, progress in public health, the discovery of antimicrobials, and the utilization of biologic products led to the recognition of genetically determined defects of Immunity and the design of effective treatment strategies. RECENT FINDINGS: The discovery of the structure of DNA, its replication, and the mapping of the human genome has transformed the field of PID into a predictable science of cutting edge therapies and diagnostic concepts. SUMMARY: This review illustrates the historic events that led to the discovery, classification, and molecular definition of PID.

History of immunoglobulin replacement.

The provision of antibodies to prevent and treat infection began with the application of "curative serum" in the first years of the last century. After the process of large-scale plasma fractionation was developed in the 1940s, the general use of immunoglobulin expanded. Intravenous immunoglobulin products became available in the 1970s, and their only use for the provision of antibodies governed the opinion of experts over the next decade. Modulation of inflammation and immunosuppression were introduced in treatment of inflammatory and autoimmune diseases and became accepted indications. The history of adverse events of treatment and their management are outlined in this article. Consensus indications and evidence-based off-label uses are discussed.

B lymphocytes: how they develop and function.

The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries.

Robert A. Good, the March of Dimes, and immunodeficiency: an historical perspective.

Dr. Robert A. Good and the March of Dimes Birth Defects Foundation maintained a close association for a quarter century in the fight against immunodeficiency diseases. The March of Dimes, whose mission is to prevent birth defects, premature birth, and infant mortality, awarded an initial grant to Dr. Good in 1960 to conduct basic clinical and experimental studies on arthritis and collagen diseases. By 1966, this support broadened to include Dr. Good's research on agammaglobulinemia, ataxia telangiectasia, Chediak-Higashi disease, and Wiskott-Aldrich syndrome. Dr. Good led three historic March of Dimes conferences on immunodeficiency and, in 1968, conducted the first bone marrow transplant to correct an immunological birth defect, memorialized by the March of Dimes in its educational film, Decision (1970). March of Dimes grants to Dr. Good for his research in cellular engineering to genetically correct the defined birth defects approached $1 million for the period 1960-1985.

Blood and marrow transplantation: a perspective from the University of Minnesota.

On the occasion of the first meeting of the Robert A. Good Immunology Society in June of 2006, I was asked to provide a perspective on the history and progress of the field of bone marrow transplantation. I was honored to provide this perspective at that meeting and subsequently in this manuscript. This review has a strong University of Minnesota bias, as Minneapolis is a place where important roots in this field were developed. Minnesota is also where I have spent my career in this field learning the excitement of laboratory research beginning as a medical student under Bob Good and Carlos Martinez in 1960, and clinical research in pediatrics under Bill Krivit and Mark Nesbit beginning in 1970. This review is dedicated to two of my recently deceased mentors: Bob Good was a pioneer in so many ways and a true giant in immunology and blood and marrow transplantation. Bill Krivit taught me a great deal about genetic diseases and the critical role of compassion and understanding patients and their families in dealing with fatal illness and new treatments such as bone marrow transplantation that are often risky and themselves may result in suffering and death. My affection for Bob Good and Bill Krivit is unending.

What caused the epidemic of Pneumocystis pneumonia in European premature infants in the mid-20th century?

An epidemic of interstitial pneumonia principally involving premature infants occurred in Germany and nearby European countries between the 1920s and 1960s. Fatalities were due to Pneumocystis. Because the principal defenses against Pneumocystis are T cells, an acquired T-cell deficiency was postulated. A number of potential causes including malnutrition were considered. All were implausible except for a retrovirus that was benign in adults but virulent in premature infants. Furthermore, we suspect that the virus was imported into Germany from former German African colonies. Premature infants were vulnerable because of the developmental status of their T cells. Given the practices in that part of Europe at that time, the virus was most likely transmitted by contaminated blood transfusions and subsequent contamination of reusable needles and syringes used in injections. Although the epidemic ended 4 decades ago, a search for the postulated retrovirus can be conducted if tissues from affected infants are available.

The discovery of agammaglobulinaemia in 1952.

UNLABELLED: Fifty years ago a new disease, agammaglobulinaemia, was described. This was made possible by a great number of preceding technical innovations and theories on different fields of research, in particular haematology, microbiology/immunology and basic sciences. The widely used name "Bruton disease" credits one single man with a new observation which, however, was simultaneously made by several physicians. Agammaglobulinaemia was the first example of an immunodeficiency syndrome (IDS). Based on new facts, new ideas emerged which in turn gave rise to innovative research, concerning both clinical observations and basic problems. Many similar diseases, usually resulting from a genetic defect, were described. Since 1970, an International Committee appointed by the WHO, has, with periodic reassessments, been working on the classification of the syndromes. All participants of an efficient immune reaction can be deficient in individual patients, that is: antibodies, lymphocytes, phagocytes and complement. Basic scientists presented striking results concerning the structure and action of all elements mentioned above. CONCLUSION: mutual stimuli coming from observations in families and from gene technology have resulted in the elucidation of the genetic defects of most IDS. Recent results of genetic engineering seem to justify some hope for success in therapy.

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.

Primary immunodeficiency diseases: dissectors of the immune system.

The past 50 years have seen enormous progress in this field. An unknown concept until 1952, there are now more than 100 different primary immunodeficiency syndromes in the world's literature. Each novel syndrome has shed new insight into the workings of the immune system, dissecting its multiple parts into unique functioning components. This has been especially true over the past decade, as the molecular bases of approximately 40 of these diseases have been identified in rapid succession. Advances in the treatment of these diseases have also been impressive. Antibody replacement has been improved greatly by the development of human immunoglobulin preparations that can be safely administered by the intravenous route, and cytokine and humanized anticytokine therapies are now possible through recombinant technologies. The ability to achieve life-saving immune reconstitution of patients with lethal severe combined immunodeficiency by administering rigorously T-cell-depleted allogeneic related haploidentical bone marrow stem cells has extended this option to virtually all such infants, if diagnosed before untreatable infections develop. Finally, the past 3 years have witnessed the first truly successful gene therapy. The impressive results in X-linked severe combined immunodeficiency offer hope that this approach can be extended to many more diseases in the future.