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IL-2 is an immune-based therapy that results in dramatic increases in CD4+ cell counts when used in conjunction with anti-HIV therapy. Although IL-2 has been discussed in previous issues of PI Perspective, new information warrants a further look at the product.
Mg participates in immune responses in numerous ways: as a cofactor for immunoglobulin synthesis, C'3 convertase, immune cell adherence, antibody-dependent cytolysis, IgM lymphocyte binding, macrophage response to lymphokines, T helper-B cell adherence, binding of substance P to lymphoblasts and antigen binding to macrophage RNA. Mg deficiency in rodents impairs IgG synthesis and cell-mediated immunity; complications include thymus atrophy, elevated IgE, hypereosinophilia, histaminosis and lymphoma. Immunologic sequelae of Mg deficiency in humans are subtle and may be affected by genetic control of blood cell Mg concentration. Abnormal C' activation, excess antibody production and susceptibility to allergy and to chronic fungal and viral infections have been reported. Mg appears to play a protective role in acute allergic reactions.
In a group of 176 apparently healthy aged people living at home (age range 62-86 years) the prevalences of monoclonal immunoglobulin and of autoantibodies did not differ from those found in other studies, but remarkably 38% of the people studied had cold lymphocytotoxic antibodies. The occurrence of serological abnormalities showed no age dependency. The participants were grouped according to serological abnormalities. The various groups showed no differences in peripheral blood mononuclear cell composition (concentration of B lymphocytes and T lymphocytes or of T lymphocyte subsets with OKT 4 and OKT 8 phenotype) or function (lymphocyte stimulation with phytohaemagglutinin, concanavalin A, pokeweed mitogen and antigen cocktail). Compared with a control group of young blood donors, the lymphocyte stimulation responses tended to be lower in the old age groups. It is concluded that, as measured in this study, humoral abnormalities during ageing are not associated with changes in B and T lymphocyte subsets or function.
A commercial formulation of chlorpyrifos was evaluated for effects on selected immune system functions in male Fisher 344 rats. Chlorpyrifos in an olive oil vehicle was administered by oral gavage twice weekly for 28 d at a dose of 5.0 mg/kg for each treatment. Body weight and organ/body weight ratios were unaffected by the chlorpyrifos. In contrast, chlorpyrifos impaired T-lymphocyte blastogenesis induced by concanavalin A (P = 0.03) and phytohemagglutinin (P = 0.023), but did not alter B-lymphocyte blastogenesis induced by lipopolysaccharide/dextran (P = 0.082. Humoral immunity (anti-sheep red blood cell), a T-lymphocyte macrophage-dependent response, was also reduced (P = 0.019) when the antibody response was expressed/10(6) spleen cells, although the response expressed/spleen was unaffected (P = 0.32), reflecting increased lymphocyte production. The total splenic lymphocyte counts in the chlorpyrifos-treated rats increased by 91% (P < 0.0001), therefore reducing the antibody response when expressed/10(6) spleen cells. Chlorpyrifos had no effect on macrophage phagocytosis (P = 0.27), but increased the relative percentage expression of CD5+ (P = 0.028) and CD8+ (P = 0.003). The presence of normal antibody and phagocytic responses in association with reduced T-lymphocyte blastogenesis and enhanced expression of specific cell surface antigens indicated that chlorpyrifos induced immune alterations associated with lymphocyte subpopulations.
The newborn immune system differs quantitatively and functionally from that of adults. Development of the immune system has important implications for childhood diseases. The immaturity of the immune system in the first years of life may contribute to failure of tolerance induction and in the development of allergic disease. T cell function is diminished, especially the capacity to produce cytokines; production of interferon (IFN)-gamma, and IL-4 is strongly reduced. IFN-gamma has been found to be even lower in cord blood of newborns with a family history of atopy. Differences in other cell types (natural killer cells, antigen-presenting cells, and B cells) could also play a role in the development of allergic disease. Current data suggest that irregularities in IgE synthesis, helper T cell subsets (Th1, Th2, CD45RA, and CD45RO), cytokines (IL-4, IFN-gamma), and possibly other cell types may play a role in the development of allergy in childhood. Moreover, the role of cell surface molecules, like co-stimulatory molecules (CD28, CD40L), activation markers (CD25), and adhesion molecules (LFA-1/ICAM-1, VLA-4/ VCAM-1) is also discussed. These variables are modulated by genetic (relevant loci are identified on chromosome 5q, 11q, and 14) and environmental forces (allergen exposure, viral infections, and smoke). The low sensitivity of current predictive factors for the development of allergic diseases, such as cord blood IgE levels, improves in combination with family history and by measurement of in vitro responses of lymphocytes and skin reactivity to allergens. New therapeutic approaches are being considered on the basis of our current understanding of the immunopathology of allergic disease, for instance cytokine therapy and vaccination with tolerizing doses of allergen or peptides.
To study the effects of different types or intensities of stressors on immune reactivity in the lungs, we studied the ex vivo production of nitric oxide (NO) and IL-1beta by alveolar macrophages (AM) after short exposure of rats to restraint stress or inescapable electric footshocks. Exposure to electric footshocks of various intensities resulted in an intensity-dependent decrease in NO production whereas the IL-1beta production by AM had increased. The secretory activity was similarly affected by restraint stress. When the time course of electric footshocks on secretory functions of AM was studied, it was found that the effects on NO and IL-1beta production by AM were normalized 3 days after the stress induction, but reappeared when cells were isolated 1 to 2 wk after stress exposure. Analysis of the effects of electric footshocks of various intensities on antibody production 10 days after the stress session and subsequent lung immunization with trinitrophenyl conjugated keyhole limpet hemocyanin (TNP-KLH), showed a footshock intensity-dependent response. Although exposure to stress induced an increase in plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hormone levels did not differ between the various stress-exposed groups. This suggests that the observed stress effects on pulmonary immune functions were not mediated by ACTH or CORT but point to a direct involvement of the autonomic nervous system.
The impairment of lymphocytes to proliferate to HIV antigen is a relatively early functional defect of cell-mediated immunity found in HIV-infected individuals. The finding of strong proliferative responses in nonprogressive HIV disease as well as its inverse association with viral load and clinical manifestation of AIDS supports the further use of this marker as a surrogate of disease progression. The observation that HIV-specific lymphocyte proliferation is associated with the production of CD8-derived HIV suppressive factors such as the beta-chemokines further supports this conclusion. These functional immune measurements provide an additional marker to monitor disease progression in HIV-infected individuals, along with the current standards of CD4 counts and viral load. Copyright 1997 S. Karger AG, Basel
Freedom from infection is the result of many tiers of immune defenses that harmoniously interact to rid the body of microorganisms and their products, which are perceived as foreign. The ability to distinguish self from nonself is embodied in lymphocytes, which serve both effector and regulatory functions. Through the elaboration of cytokines and immunoglobulins, lymphocytes recruit nonspecific immune effectors, focus their activity, and modulate the intensity of the immune response. The phylogenetically more primitive complement system serves a similar function. Although congenital defects in immune function occur, by far the most common causes of immunodeficiency are acquired and occur in patients treated for cancer with myelosuppressive, cytolytic drugs and in transplant recipients treated with immunosuppressants. HIV infection and malnutrition are responsible for even larger numbers of immunocompromised patients worldwide. The nature and severity of infections that occur as a result of immunodeficiency vary as a function of the immune effector targeted and the degree to which it is dysfunctional. Granulocytopenia is well tolerated unless the absolute number of circulating cells falls below 500/mm3. Profound granulocytopenia and deficits of neutrophil function are often manifest as bacterial or fungal infections. Complement deficiency predisposes to infection with encapsulated bacteria such as pneumococci, meningococci, and Haemophilus influenzae. T cells play such a central role in the immune response that their derangement is associated with susceptibility to almost any potential pathogen. These patients often succumb to mortal opportunistic infections. Recent advances in hybridoma and recombinant DNA technology have provided us with immunologic reagents that enable us to manipulate the immune response. Anti-CD3 monoclonal antibody has permitted salvage of solid organ transplants in well-defined clinical settings. Monoclonal antibodies against TNF-alpha and lipopolysaccharide may alter the consequences of gram-negative sepsis. Alternatively, recombinant cytokines have been associated with clinically significant tumor regression in selected patients, presumably by enhancing the nascent antitumor immune response. The development of immunologic reagents such as these in concert with our growing understanding of the immune system may translate to improved care for immunocompromised patients.
Cyclophosphamide is widely used to induce a remission of minimal-change nephropathy, but concerns have been raised about whether its effects on cellular immunity persist after treatment is discontinued. We studied functional and numerical measures of cellular immunity in children who had minimal-change nephropathy with frequent steroid-responsive relapses and were receiving cyclophosphamide (2.5 mg per kilogram of body weight per day for eight weeks). Sequential studies during such treatment showed that cyclophosphamide caused lymphopenia, particularly among T helper cells, resulting in a significant fall in the immunoregulatory (helper/suppressor) cell ratio. This change persisted 1 to 3 months after cyclophosphamide was discontinued, but measures of immune function reverted to normal after 6 to 12 months. Children with minimal-change nephropathy in long-term remission had no difference in T-cell subpopulations, lymphocyte responses to mitogens, or suppressor-cell function that could be attributed to the disease itself or to the previous use of cyclophosphamide.
Ageing in immune reactivity is described at the level of lymphoid cells, at that of lymphoid organs and organ function, and at that of regulation of cell and organ function. Apart from shifts in numbers of lymphoid cell subpopulations, the decrease in communication capacity between lymphoid cell populations and in binding of invaders (like bacteria) is an important aspect of ageing. These aspects may contribute to the decreased immune reactivity to invaders and the enhanced incidence of immune reactions to self-components (autoimmune reactivity). Studies on the physiology and pathophysiology of ageing in the immune system lead to improvement in prevention and therapy of immunological diseases of ageing, with prospect on an enhanced life quality of aged people and an extension of the mean lifespan of man.
General cell-mediated immune (CMI) functions in NPC patients were investigated by the in vivo Mantoux and in vitro lymphocyte response to PHA assays. Thirty-eight (50%) of 76 untreated NPC patients were hyporesponsive in the Mantoux assay compared to 27 (25%) of 110 control patients. Forty-three (65.2%) of 66 untreated NPC patients also showed lymphocyte hyporesponsiveness to PHA compared to 15 (15.5%) of 97 control patients. Combined deficiencies were observed in 35 (42.2%) of 83 NPC patients compared to only 2 (3.3%) of 61 control patients. No difference in the frequency of immunodeficiency was observed between "early" and "late" disease patients. CMI functions of treated "remission" NPC patients were found to be impaired to the same extent as those of untreated NPC patients.
Atopic dermatitis (AD) is a pruritic, chronically relapsing skin disease in which Th2 cells play a crucial role in cutaneous and extracutaneous immune reactions. In humans, CD11c+CD123- myeloid dendritic cells (mDC) and CD11c-CD123+ plasmacytoid DC (pDC) orchestrate the decision-making process in innate and acquired immunity. Since the number and function of these blood dendritic cell (DC) subsets reportedly reflect the host immune status, we studied the involvement of the DC subsets in the pathogenesis of AD. Patients with AD had an increased DC number and a low mDC:pDC ratio with pDC outnumbering mDC in the peripheral blood compared with normal subjects and psoriasis patients (a Th1 disease model group). The mDC:pDC ratio was correlated with the total serum IgE level, the ratio of IFN-gamma-producing blood cells:IL-4-producing blood cells, and the disease severity. In vitro allogeneic stimulation of naive CD4+ cells with atopic DC showed that the ability of pDC for Th1 induction was superior or comparable to that of mDC. In skin lesions, pDC infiltration was in close association with blood vessels expressing peripheral neural addressins. Therefore, compartmental imbalance and aberrant immune function of the blood DC subsets may deviate the Th1/Th2 differentiation and thus induce protracted allergic responses in AD.
UNLABELLED: Opioids such as morphine are the mainstay of acute and chronic pain treatment. The purpose of this study was to investigate the immunosuppressive effects of morphine in patients with pain syndromes. We investigated 10 patients with chronic pain syndromes undergoing treatment with oral sustained-release morphine (30-240 mg/d) before and after 1,4, and 12 wk of treatment compared with healthy control subjects without morphine treatment. Immunological variables of the cellular and humoral immune axis showed that 1) total lymphocyte counts and the distribution of lymphocyte subpopulations, including helper T-cell/suppressor cytotoxic T-cell ratios (CD4/CD8 ratios), did not change compared with baseline or healthy control subjects; 2) proliferation of peripheral mononuclear cells (PMC) was not impaired by morphine treatment; 3) interleukin 2 production increased after 4 wk of treatment with morphine; and 4) immunoglobulin (Ig) production was reduced before initiation of therapy in pain patients and decreased further during morphine treatment, whereas Ig concentrations in the circulation remained at normal levels. These results indicate that treatment with oral, sustained-release morphine does not have a suppressive effect on overall PMC function. On the other hand, Ig production was impaired in patients with chronic pain and was further suppressed by morphine. Whether this suppression of humoral immune function has a clinical impact on the immune system as a whole remains to be determined. IMPLICATIONS: Treatment of patients with chronic pain with oral, sustained-release morphine does not influence cellular immune function, but it suppresses the already attenuated production of immunoglobulins.
Chronic malnutrition is one of the most important causes of several metabolic, immune and neuroendocrine dysfunctions. The aim of the present study was to determine the influence of chronic food restriction on basal neuroendocrine, immune and adipocyte functions and during the acute-phase response to endotoxic shock in female rats. The effect of refeeding of undernourished rats on the above-mentioned functions was also investigated. For these purposes, plasma total protein, glucose, triglycerides, ACTH, corticosterone, tumor necrosis factor-alpha (TNF) and leptin (LEP) levels were determined in basal condition and 2 h after endotoxin (LPS; 180 microgram/kg body weight, i.p.) administration in 3 different groups: (1) well-nourished (WN) controls; (2) undernourished (UN) rats as a consequence of chronic food restriction, and (3) UN rats re-fed to restoration of their body weights in the WN rat range. The results indicate that UN rats, in comparison with WN controls, developed an arrest in body weight gain as well as in basal hypoglycemia, hypotriglyceridemia, hypoleptinemia, hypercorticosteronemia and enhanced adrenal glucocorticoid content; however, no changes in basal total protein, ACTH and TNF plasma levels and in anterior pituitary ACTH concentrations were found. When endotoxic shock was induced, the LPS-induced hypoglycemia developed in WN rats was abolished in UN animals, and both ACTH and TNF plasma concentrations after endotoxin, albeit significantly (p < 0.05) higher than the respective basal values, were significantly (p < 0.05) lower in UN than in WN control rats. Despite the high basal plasma corticosterone concentration in UN vs. WN rats, the LPS-induced glucocorticoid release was similar in WN and UN rats. Additionally, LPS treatment did not modify basal plasma LEP levels, regardless of the group. Interestingly, UN rats fed ad libitum for 15 days restored their body weight to WN rat range values, and the various metabolic dysfunctions seen in UN rats in both basal and post-LPS conditions were fully normalized. Our results clearly indicate that chronic undernutrition not only affects, as earlier described, reproductive function but also metabolic, neuroendocrine, immune and adipocyte functions, and that the effects induced by undernutrition can be fully reversed after recovery of normal body weight. The present study strongly supports the involvement of the metabolic status in the effectiveness of the defense mechanisms developed in patients in inflammatory stress conditions.
To clarify the relationship between purine metabolism and immunity, the in vivo immunosuppressive effects of allopurinol (AL), a xanthinoxidase (XO) inhibitor, were studied using normal BALB/c and severe combined immunodeficient (SCID) mice. Following AL administration for 14 weeks (long term), a decreased immune response to ovalbumin (OVA) in the peripheral blood was observed in normal mice, which might not be only due to direct B cell suppression but also due to suppression of helper T cell function. In the SCID mice, there was a markedly late and reduced recovery of surface immunoglobulin (sIg) positive cells, which are markers for mature B lymphocytes, in the peripheral blood after AL administration. The total immunoglobulin G (IgG) titers in the AL treated group were significantly lower than in the control group 6 weeks after stem cell transfer, but increased until there was no difference in the titers between the two groups at week 14. CD4 positive helper T cells and CD8 positive T cells were slow to recover, though these gradually recovered to reach normal levels in the mature stage. These data suggest that the administration of AL may modulate B cell and T cell responses in OVA-immunized antibody formation. Furthermore, this study showed that AL could influence immune functions during the pre-natal and developmental periods and that its effects might differ according to the stages of maturity of the immune cells.
Multiple communicative pathways among nervous, endocrine, and immune systems facilitate physiological immunoregulation. Spinal cord injury (SCI) patients had strikingly decreased natural and adaptive immune responses by 2 weeks post injury. While NK-cell function was decreased, plasma ACTH and urine-free cortisol levels were increased. T cell function and activation were both diminished. With rehabilitation therapy, NK and T function increased; without rehabilitation, NK levels remained depressed. When rehabilitation ceased, NK function decreased. Cervical SCI patients had less NK and T function than thoracic injury patients. SCI patients also had reduced levels of cellular adhesion molecules (CAMs) that participate in immune function and wound healing. SCI patients with pressure ulcers were compared to those without pressure ulcers. LFA-1, VLA-4, and other surface markers were decreased on the lymphocytes of all SCI patients. SCI patients with pressure ulcers had lower CAM levels than did patients without pressure ulcers. Nutritional status was determined by zinc, albumin, and prealbumin levels. SCI patients had decreased albumin levels. Those with pressure ulcers had decreased prealbumin levels and zinc levels.
Immune responses within the mammalian gonads, and in particular the testis, are deficient in spite of adequate lymphatic drainage and the presence of lymphocytes and MHC II+ macrophages. There is considerable evidence from in vivo and in vitro studies that this 'suppression' of the immune system may be due, at least in part, to localized inhibition or regulation of normal lymphocyte and/or macrophage functions within the gonads. In the testis, both steroidal and non-steroidal products of the Leydig cells, including androgens, endorphins, and inhibin-related proteins, have been implicated in mediating this activity. In turn, a number of immune cell cytokines affect steroidogenic cell function in vitro. The studies described in this paper indicated that [3H]-thymidine incorporation by adult rat thymocytes in vitro was inhibited by conditioned medium collected from short-term incubations of Percoll-purified adult rat Leydig cells, but stimulated by testicular interstitial fluid and by conditioned medium collected from short-term incubations of adult rat seminiferous tubules. The factors responsible for these effects on thymocyte function appeared to be of large molecular weight, as they were retained by ultrafiltration membranes with exclusion limits of 10,000 or 30,000 daltons. It is hypothesized that an 'immunosuppressive' mechanism, principally mediated by non-steroidal factors secreted by the steroidogenic cells of the gonadal interstitial tissue, exists within the gonads in order to prevent activation of the immune system by germ cell antigens and growth factors associated with germ cell proliferation and differentiation. This mechanism probably acts in parallel with normal antigen-specific tolerance mechanisms operating at the gonadal level. As immune responses to germ cells are believed to be a significant causative factor in infertility, particularly in men, this represents an important area for further study.
Intense physical exercise has been shown to be associated with immunosuppression and increased rate of infection. The immunosuppressive effect of exhaustive exercise has been attributed to a reduced helper/suppressor T-cell ratio, low salivary levels of immunoglobulin-A, decreased lymphocyte proliferative response and natural killer cell activity, and elevation of stress hormones. Yet some athletes can withstand intense training periods without health problems while others are prone to infections. Thus it has been postulated that other factors may interfere with immunoregulation. The notion that macro- and micronutrients are involved in the regulation of immunological processes and the ability to cope with muscular and systemic exercise stress has been gaining attention. Particularly trace elements have been shown to be related to cell mediated and humoral immunity such as NK-cell activity, T- and B-cell functions, and cytokine release. Many investigations have reported decreased concentrations of trace elements in blood and tissues after training and competition. However, the magnitude of losses is highly dependent on the type and intensity of exercise, the individual regulatory state, and most important, nutrition. This paper reviews the data on zinc, iron, and magnesium status in athletes and summarizes the consequences of deficiencies in these trace elements regarding exercise tolerance and immune function. These elements were chosen since there is evidence they are related to exercise-induced stress and immune function.