The therapeutic implications of the hypothesis of allergic hypersensitivity as dysfunction of the intracellular immune mechanism.
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Adrenal Cortex Hormones↗
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Tumor-host immune interactions and dendritic cell dysfunction.
Several lines of evidence from recent years support the existence of cancer immunosurveillance, especially studies of natural killer (NK) cells and the IFN-gamma pathway. However, immune suppression is clearly observed in cancer patients and tumor-bearing animals as well. The fact is that although cancers often elicit a vigorous immune response during the early part of their growth, the immune response is soon down-regulated, permitting progressive tumor growth. Apparently, the intrinsic plasticity of tumors allows the immune system to sculpt the immunogenic phenotypes of tumors to escape efficient immune destruction. But most evidently, several mechanisms have now been found to contribute to the failure of immune control of tumor growth. Tumor cells have a very low level of MHC class II, costimulatory molecules, and weak antigens. They also produce immune suppressive factors (VEGF, IL-10, PGE(2)) that exert systemic effects on immune cell function. In particular, disabled dendritic cell differentiation, maturation, migration, and function are fundamental to this defect, as they are the most potent antigen-presenting cells (APCs) of the immune system, interacting with T and B lymphocyte as well as NK cells to induce and modulate immune responses. In addition, tumors also alter host hematopoiesis and produce large numbers of immature dendritic cells, and evidence shows that these cells are directly immune suppressive. Harnessing the immune system for effective cancer therapy has remained a great challenge. DC-based vaccines, or DC-based vaccines in combination with treatments designed to improve the host immune environment, may offer hope for more effective cancer immunotherapy. Tumor-host interactions are an important determinant of tumor behavior and response to therapy. How tumors interact with their hosts is thus a very broad and complex topic. In this chapter, we will focus on tumor-host immune interactions and the roles of dendritic cell dysfunction in tumor avoidance of host immune responses. We will survey recent findings regarding tumor immune surveillance, antitumor host immune responses, and how the immune system also functions to promote or select tumor variants with reduced immunogenicity. We will then discuss immune suppression caused by tumors, which is clearly observed in tumor-bearing animals and cancer patients. Finally, we will discuss altered dendritic cell function and differentiation in some detail, as it is likely to be one of the most fundamental mechanisms by which tumors escape immune responses.
Animals↗
[Cellular immunity and T-cell dysfunction syndromes].
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Aged↗
Histiocytosis X. Langerhans' cell histiocytosis.
Histiocytosis X is a complex and poorly understood entity. Nevertheless, it would appear as if certain themes are found recurrently throughout the literature dealing with this disease and a review of them serves as a useful summary. 1. Problems with Nomenclature. To name or categorize a disease based on end-organ pathology is generally not clinically useful, but this is what we have done with histiocytosis X. It has caused substantial confusion among physicians and patients alike concerning diagnosis, prognosis, and treatment. Further attempts at improving the nosology of this disease will not be useful unless those new names also reflect scientific advances in our understanding of etiology, pathogenesis, and therapy. 2. Identification of the Langerhans' Cell as the Consistent Pathognomonic Cell in the Lesions of Histiocytosis X. Although the Langerhans' cell was identified more than a century ago, it has only recently been recognized as the cell that proliferates in this disease. Nevertheless, several important questions remain regarding the relationship of the Langerhans' cell to histiocytosis. Foremost among these questions is whether the Langerhans' cell is a truly normal Langerhans' cell, responding appropriately to immune system signals, or if it is an abnormal variant, possibly even neoplastic. 3. Recognition that Immune System Dysfunction Is a Critical Part of Histiocytosis X. The immune system is the focus of most recent clinical research. Results of these studies are obviously important with regard to both the biology and management of this disease. 4. Histiocytosis X Is an Extremely Heterogeneous Clinical Disorder. As mentioned before, the term histiocytosis X was originally intended by Lichtenstein to describe a pathologic, and not clinical, entity. It is rare to find two patients with this disease who are exactly alike. To make matters even more confusing, the disease includes both infants with disseminated fatal disease as well as middle-aged adults with solitary bony lesions. 5. The Disease Requires Improved Therapy, but it Is a Difficult Setting in which to Perform Clinical Studies. Improved therapy is required in patients with this disease, especially those with the disseminated form. But it will be difficult to develop improved therapy until definitive answers are provided to some of the basic questions of etiology and pathogenesis. Unfortunately, these clinical studies are not readily available because of the rare occurrence of this disease and its extreme clinical heterogeneity.(ABSTRACT TRUNCATED AT 400 WORDS)
Bone Neoplasms↗
Pulmonary edema induced by fluid administration in acquired immune deficiency syndrome patients with cardiac autonomic dysfunction.
Two patients with the acquired immune deficiency syndrome developed acute pulmonary edema following intravenous fluid administration. Both recovered with diuretic therapy. In neither case was there evidence of persistent severe left ventricular dysfunction, nor was there evidence (either clinically or by thallium study) of flow limiting coronary lesions or of cardiac uptake of iodine-123 meta-iodobenzylguanidine, pointing to ventricular sympathetic neuropathy. It is hypothesized that destruction of the cardiac sympathetics contributed importantly to the development of pulmonary edema following the intravenous fluid load.
3-Iodobenzylguanidine↗
Pathways to a robust immune response in the elderly.
Circumstantial evidence suggests that infectious disease is the major cause of morbidity and mortality in the elderly, and immune-system dysfunction may contribute to this finding. Because innate and humoral immunity seem to be relatively unaffected by aging and because the T-cell compartment shows marked age-associated alterations, this article focuses on the association between T cells and aging. Longitudinal studies suggest that immune parameters, which predominantly are related to T cells, can be clustered to yield an IRP that is predictive of mortality in the elderly. Determining the IRP also may be helpful in younger individuals, particularly those under chronic antigenic stress (eg, patients with cancer or chronic infections) who experience premature aging of the immune system. Some changes in T cells can be modeled in clonal cultures in vitro to discover new biomarkers of immune aging. These biomarkers, which need to be validated in vivo, could be used to refine IRP. Interventions to selectively target changes that are identified as part of IRP may improve the health and quality of life of the elderly, reduce healthcare costs, and avoid potential unwanted side effects of global intervention approaches, such as triggering or exacerbating autoimmunity and inflammation.
Aged↗
[Immunomorphologic characteristics of bedsores].
Biopsies and blood of 36 patients with bedsores developing due to spinal cord trauma were studied. Pronounced alterations in the blood content of IgA, IgM, IgG, a significant increase in circulating immune complexes (CIC) content and a decrease of neutrophil leukocyte chemotactic activity were found. The authors conclude that an immune system dysfunction occurs in patients with bedsores as well as secondary immune deficiency and immunoglobulin and CIC deposition in the granulation tissue vessels. Development of chronic vasculitis, obliteration and reduction of vessels, hypoxia and metabolic disturbances in the wound edges, formation of deficient fibroblasts synthesizing collagen type III which does not facilitate skin epithelium maturation, all these changes result in a chronic course of the wound and almost complete lack of healing.
Adult↗
[The effect of trauma surgery on immune system function].
Severe accidental trauma often causes an immunosuppression accompanied by infection and sepsis which may be fatal. Furthermore, elective surgery could also cause dysfunction of the immune system. While physiopathological mechanisms of such posttraumatic immune system dysfunctions are still not sufficiently understood, the scope of research interest is focused particularly on the cytokine network and, recently, on the "nonspecific" mediators of oxidative stress. In this article some novel findings about the dysfunction of the immune system caused by trauma, including surgical injury, are briefly summarized, and the involvement of oxidative stress in these changes is emphasized.
Animals↗
The pathophysiology of biliary obstruction and its effect on phagocytic and immune function.
These studies have direct clinical relevance to the multisystem deficits seen in mechanical biliary obstruction (Fig. 3). Defects in two crucial elements of effective phagocytosis (chemotaxis and intracellular killing) have been demonstrated in obstructive jaundice. At the same time, complete diversion of bile (containing bile salts and s-IgA) from the gut lumen causes changes in the endogenous bacterial flora, loss of mucosal integrity, and decreased endotoxin inactivation, resulting in portal bacteremia, endotoxemia, and increased translocation to mesenteric lymph nodes. This increased load comes at a time when the liver is metabolically impaired and RES function is abnormal. Decreased hepatic clearance of intrabiliary bacteria may contribute to the development of cholangitis (by both ascending and hematogenous routes). Inadequate RES control of portal bacteremia results in "spillover" with subsequent systemic bacteremia and localization of organisms in the lungs where they may contribute to pulmonary dysfunction or pneumonia. Although reversal of jaundice is readily accomplished by either external or internal biliary drainage, chronic biliary obstruction results in functional alterations in the liver which are reversed, generally incompletely, only after weeks or months of decompression. External biliary decompression fails to restore the enterohepatic circulation, preventing bile salts, s-IgA, and other substances from entering the lumen of the gut. It is not as effective as internal biliary drainage in reversing RES dysfunction or restoring immune parameters. Even with internal drainage, restoration of normal function in these systems takes weeks or months. Muramyl dipeptide analogues show some promise. A possible unifying mechanism may provide the clues to further experiments which will suggest better ways of reducing the morbidity and mortality in these patients. All macrophages share common functions which include not only phagocytosis but also antigen processing and the production of cytokines. The immune dysfunction noted in obstructive jaundice may be due to inadequate or inappropriate antigen processing or cytokine production by macrophages or to abnormal hepatocyte-Kupffer cell interactions. Kupffer cells are the largest pool of macrophages. Most numerous in periportal areas, Kupffer cells process significant quantities of enteric-derived antigens and Kupffer cell blockade results in an exaggerated response to these antigens. Kupffer cells also act as important scavengers of endotoxin, which stimulates the release of TNF and IL-6.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Nutrition: a cofactor in HIV disease.
The relationships among nutritional status, infectious disease, and the immune system suggest that nutrition may be a cofactor in human immunodeficiency virus (HIV) progression. We examined nutrition as a cofactor in HIV disease by reviewing the current literature on the interactions of nutrition, infectious disease processes, and immune system dysfunction. Studies demonstrate that poor nutritional status and infection affect the immune system and interact with each other. This relationship leads to the development of opportunistic infections and malignancies, which may result in a diagnosis of acquired immunodeficiency syndrome. Moreover, evidence from our review indicates that nutritional status may play a role in HIV disease progression. We recommend that clinical trials be conducted to evaluate general malnutrition and the efficacy of supplementation with specific nutrients at various stages of HIV disease.
HIV Infections↗
The immune system in hearing disorders.
Cellular and humoral immune reactions may play a role in the ethiopathogenesis of audiovestibular dysfunction. Immune-mediated inner ear disorders can be of cochlear and retrocochlear origin. Autoimmunity plays a certain role, but is certainly not obligatory. Anti-inflammatory treatment remains the mainstay of therapy. Such hearing disorders can further be looked upon as 'experiments of nature'.
Autoimmune Diseases↗
Increased urinary zinc excretion in cancer patients is linked to immune activation and renal tubular cell dysfunction.
Urinary zinc excretion is known to be increased in cancer patients, but the pathogenesis of this phenomenon remains uncertain. Both skeletal muscle catabolism and renal tubular cell dysfunction have been proposed to explain this observation. We have investigated urinary zinc and N-acetyl-beta-D-glucosaminidase (NAG), an indicator of renal tubular cell dysfunction, as well as serum neopterin, an index of systemic immune activation, in 22 patients with cancer and seven controls. Both serum neopterin and urinary zinc were significantly elevated in cancer patients (15.8 +/- 12.7 versus 7.3 +/- 2.3 nmol l-1 and 1.77 +/- 0.80 versus 1.21 +/- 0.41 mmol mol-1 creatinine, P < 0.02 and P < 0.05, respectively), while NAG was similar in cancer patients and the controls (13.58 +/- 13.80 versus 13.68 +/- 12.19 mu kat mol-1 creatinine). A significant correlation was observed between serum neopterin and urine zinc (rs = 0.5119, P < 0.02), serum neopterin and urine NAG (rs = 0.6761, P < 0.002), and urinary zinc and NAG (rs = 0.6348, P < 0.002). In conclusion, the present data indicate a link between urinary zinc excretion and immune activation as well as renal tubular cell dysfunction. In addition, renal tubular cell dysfunction appears to be linked to immune activation.
Acetylglucosaminidase↗
The ovary as an immune target.
The ovary does not have a distinct morphologic barrier between the immune system and the developing gametes. This is in contrast to the testis in which the junctional complexes between the Sertoli cells form the blood-testis barrier. Whereas there are numerous factors, including genetic ones, associated with ovarian dysfunction, the immune factors have frequently been implicated in ovarian dysfunction. Much of our knowledge used to evaluate the immune system of the ovary has come from studies on the expression of the zona pellucida (ZP) proteins during ovarian development. Initial studies by Dunbar and colleagues demonstrated that immunization of rabbits with porcine ZP proteins (but not rabbit ZP proteins) would result in the generation of antibodies that inhibit sperm binding to the ZP and interfere with normal ovarian follicular development. In contrast to the rabbit and primate models, immunization of mice or rats with porcine ZP proteins does not have an effect on fertility or ovarian function although immunization of certain strains of mice with mouse ZP peptides and immune activator systems has been shown to result in ovarian pathology. Whereas immune inflammatory reactions have been observed in the mouse models, no such immune reactions have been observed in rabbit, guinea pig, or nonhuman primate models. Subsequent observations in nonhuman primates have shown that immunization of primates with ZP proteins expressed from cDNAs coding for the mouse and rabbit ZP2 (the mouse homologue has 60% amino acid identity with human ZP2) or the mouse ZP3 (the mouse protein has 67% amino acid identity with human ZP3) causes ovarian dysgenesis. In contrast, immunization of primates with recombinant rabbit ZP1 protein (the mouse homologue has 39% amino acid identity with human ZP1) does not affect nonhuman primate ovarian function or follicular development but will elicit antibodies that inhibit sperm binding to the primate ZP. These studies have collectively provided important information concerning the immunologic status of the ovary and demonstrate the species variations in immune responses to different ovarian immunogens.
Animals↗
Drug evaluation: tesamorelin, a synthetic human growth hormone releasing factor.
Theratechnologies, under license from Valeant, is developing tesamorelin as a potential vaccine adjuvant and for the potential treatment of wasting, hip fracture recovery, immune disorders, HIV-related lipodystrophy, sleep maintenance insomnia and mild cognitive impairment. Phase III clinical trials for the treatment of HIV-associated lipodystrophy and phase II clinical trials for sleep disorder, chronic obstructive pulmonary disorder, hip fracture and immune system dysfunction are underway. Phase II trials are also assessing the influenza vaccination immune response and cognitive effects of tesamorelin.
Adjuvants, Immunologic↗
Immunology of hearing: experiments of nature.
Cellular and humoral immune reactions may play a role in the ethiopathogenesis of an audiovestibular dysfunction. Immune-mediated inner ear disorders can be of cochlear and retrocochlear origin. Autoimmunity plays occasionally a role, but is certainly not obligatory.
Antibody Formation↗
Immune response, nitric oxide, autonomic dysfunction and stroke: a puzzling linkage on Trypanosoma cruzi infection.
Trypanosoma cruzi (T. cruzi) is a tissue parasite causing American trypanosomiasis or Chagas' disease (ChD) affecting, mostly, the cardiovascular and gastrointestinal systems. We have recently found that people infected by T. cruzi are also more prone to developing ischemic strokes than the general population, even without heart complications; the pathomechanism of it is not yet well understood. However, after infection occurs, immune response induces endothelial dysfunction due to an endothelial nitric oxide synthase (eNOS) inhibition and increased activity of inducible nitric oxide synthase (iNOS). These factors are active in inducing vasoconstriction and cerebral microvascular spasms, leading to ischemic stroke. In addition, patients with ChD, regardless of cardiopathy, also have autonomic dysfunction, all of which may enhance the risk of developing ischemic stroke. Moreover, the possibility that these neuroimmunomodulatory pathways are disturbed in patients with other types of stroke seems possible, and is worthy of investigation.
Animals↗
Intravenous nutritional support and the surgeon: where next?
Over the past twenty five years the development of total parenteral nutrition has in many ways revolutionised the practice of surgery. It has enhanced survival in otherwise high mortality operations such as oesophageal surgery, especially with anastomotic complications. It has changed significantly the management of fistulae, either post operative or associated with diseases such as Crohn's enteritis. Here a basic general principle is applied--that a fistula will close if there is no distal obstruction and the throughput can be diminished. This can be achieved by withholding oral feeding and using the parenteral route. It has allowed survival in the short gut syndrome from whatever cause and it is interesting to see the degree of "intestinal adaptation" that occurs once the first critical year is survived with the help of intravenous nutrition. The assessment of nutritional status is difficult and while the level of serum albumin may be taken as a clinical standard, it is obvious that many patients survive extensive surgery with low albumin levels and also that there appears to be a lag period to the restoration of albumin levels, even with otherwise successful nutritional support and with other parameters being satisfactory. Even complex formulae using a combination of laboratory and antropometric parameters is not fully satisfactory as an absolute assessment of nutritional status. It is now interesting to see that nutrition can affect both immune competence and even carcinogenesis. The lipid element in intravenous nutrition may cause dysfunction of immunity and vitamin status, gastric and platelet function with impaired oxygen diffusion leading to increased wedge pressures.(ABSTRACT TRUNCATED AT 250 WORDS)
Critical Care↗
mRNA mutations of type I protein kinase A regulatory subunit alpha in T lymphocytes of a subject with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by multiple T lymphocyte immune effector dysfunctions. Protein kinase A (PKA) isozymes contribute to the regulation of T cell immune effector functions. In SLE T cells, there is a profound deficiency of PKA-I isozyme activity characterized by both reduced RI alpha transcript and RI alpha protein levels. To identify a molecular mechanism(s) for this isozyme deficiency, we utilized single-strand conformation polymorphism (SSCP) analysis to detect structural changes in the cDNA. Of 10 SLE subjects, cDNAs from a single subject revealed a shifted band. Sequence analyses demonstrated that a shifted SSCP band from SLE T cells carried heterogeneous transcript mutations, including deletions, transitions and transversions. Most of these transcript mutations are clustered adjacent to GAGAG motifs and CT repeats-regions that are susceptible to transcript editing and/or molecular misreading. By contrast, no genomic mutations were identified. These results suggest the occurrence of mRNA editing and/or defective function of RNA polymerase in a subject with SLE. Mutant RI alpha transcripts are pathophysiolgically significant, for they can encode diverse, aberrant RI alpha isoforms, including truncated, dominant-negative subunits, resulting in deficient PKA-I activity. We propose that deficient PKA-I isozyme activity contributes to the pathogenesis of SLE by hindering effective signal transduction and impairing T cell effector functions.
Codon↗