Depressed Immune Response Research Articles

Modulation of the host's immune response to Plasmodium berghei by a parasite-derived immunosuppressive factor.

It is well known that Plasmodium-infected hosts are immunosuppressed, as show by their depressed immune responsiveness to a variety of antigens. It is not known, however, whether the immune response of malaria-infected animals to the malarial parasite itself is suppressed. The availability of a noninfectious, immunosuppressive factor (ISF) derived from Plasmodium berghei-infected rat erythrocytes made it possible to investigate this question. Mice infected with P. berghei and injected with the ISF had higher levels of parasitemia and shorter survival times than control mice that were similarly infected but were treated with control material derived from noninfected rat erythrocytes or with saline solution. Conversely, mice immunized against the ISF and then infected with P. berghei had lower parasitemias and longer survival times than mice immunized with the control material or with saline solution. We conclude that immunosuppression in murine malaria affects the course of malaria infection.

Infection and immunity in Down syndrome: A trial of long-term low oral doses of zinc

To determine whether orally administered zinc supplements could correct the abnormal humoral and cell-mediated immunity of Down syndrome, we randomly assigned 64 children with Down syndrome, aged 1 to 19 years and living at home, to receive either zinc gluconate or placebo daily for 6-month periods with crossover from one regimen to another. Control subjects were siblings and age-matched, unrelated children. Serum zinc, copper, and measures of immune system competence were tested at 3- or 6-month intervals. Parents kept daily logs of clinical symptoms such as cough and diarrhea and of physician visits. Mean serum zinc concentrations increased to about 150% of baseline during zinc supplementation, but we found no effect on serum levels of copper, immunoglobulins, or complement; on lymphocyte number or subset distribution; or on in vitro response to mitogens. Children with Down syndrome who were receiving zinc had a trend toward fewer days or episodes of cough and fever but no change in other clinical variables. Long-term, low-dose oral zinc supplementation to improve depressed immune response or to decrease infections in children with Down syndrome cannot be recommended.

Role of Aflatoxins as Immunomodulators

Mycotoxins in general and aflatoxins in particular are being studied as health hazard for man and animals including poultry. Aflatoxins have been found to cause biliary hyperplasia, hepatic necrosis, icterus, haemorrhage, hepatocellular neoplasia and prolongation of coagulation time. Besides these conditions, aflatoxins have been found to act as immunosuppressors. This immunosuppressive action appears to be antigen specific.Several mechanisms have been postulated. These include inhibition of RNA polymerase, increase in the activity of lysosomal enzymes, inhibition of reticulo-endothelial system and inhibition of specific immunological systems.Aflatoxins have been found to modulate the immune response to Rinderpest virus in cattle. Cattle affected with aflatoxicosis present a depressed humoral immune response to tissue culture adapted rinderpest virus vaccine. Similarly immune response to Newcastle disease virus in chicks was found to be suppressed by aflatoxins.The possible mechanisms for specific immunosuppression require an indepth study and therefore assumes great significance. Specific immunosuppression of B cells by aflatoxins could be because of specific interaction between the aflatoxins and specific markers on certain clones of B cells. Involvement of specific membrane immunoglobulins could not be ruled out.Since aflatoxins are known to depress reticulo-endothelial system macrophages are liable to be affected by aflatoxins. Consequently, macrophage mediated host defense mechanism could suffer.The above facets of the problem have been discussed.

Clinical and immunologic aspects of FeLV-induced immunosuppression

Cats exposed to the feline leukemia virus (FeLV) may mount an effective immune response and eliminate the virus, develop a non-viremic, latent infection or become persistently infected and shed the virus. Persistently infected cats commonly die of secondary opportunistic infections that result from FeLV-induced immunosuppression. The acquired immunosuppression is the most frequent and most devastating consequence of FeLV infection in the cat. Immunosuppression is targeted primarily to the cell-mediated immune system and has been attributed to the viral p15e envelope protein. The decreased IgG response and proliferative response to T cell mitogens is thought to be due to a defect in the helper cell function. As a result of T helper cell immunosuppression, infected cats may also have defective cytotoxic lymphocyte and activated macrophage functions which are regulated by their lymphokines. Research has shown that the virus causes a general suppression in the production of T cell-derived lymphokines, including gamma interferon and interleukin 2. A decrease in the function of polymorphonuclear leukocytes has also been reported and may contribute to deaths due to opportunistic infections in FeLV-positive cats. There are numerous parallels between the acquired immunodeficiency syndrome (AIDS) in man and the FeLV-induced immunodeficiency syndrome in cats. Frequent deaths due to opportunistic infections, lymphopenia, depressed cell-mediated immune responses to T cell-dependent antigens despite hypergammaglobulinemia and the presence of a long period of time between infection and the onset of clinical signs are just a few of the syndromes that are similar between the 2 retroviral diseases. A new strain of FeLV, FeLV-FAIDS has been associated with a naturally occurring immunosuppressive syndrome that is strikingly similar to AIDS in man. In addition, a T-lymphotropic retrovirus has recently been identified from cats with an immunodeficiency-like syndrome; this feline lentivirus disease is morphologically similar, but antigenically distinct from the human immunodeficiency virus, the cause of AIDS. Treatment for FeLV immunosuppression is primarily supportive. The development of a soluble tumor cell antigen vaccine has been shown to be efficacious in preventing FeLV infections.

Characterization of efferent T suppressor cells induced by Paracoccidioides brasiliensis-specific afferent T suppressor cells.

Previously, we reported that Paracoccidioides brasiliensis culture filtrate antigen (Pb.Ag) when injected i.v. into mice induces antigen-specific suppressor cells which down-regulate the anti-P. brasiliensis delayed-type hypersensitivity (DTH) response. The suppressor cells are present in both spleens and lymph nodes of Pb.Ag-treated animals and suppress the afferent limb but not the efferent limb of the DTH response to P. brasiliensis. The suppressor cells induced by Pb.Ag are L3T4+ Lyt-1+2- I-J+ T cells and are considered to be equivalent to the Ts1 cells described for other antigen-specific suppressor cell pathways. This report provides data which show that Ts1 cells induced by Pb.Ag or a soluble factor derived from Ts1 cells (TsF1) stimulates the production of second-order or efferent suppressor cells. The second-order suppressor cells are detectable in spleens and lymph nodes of mice 7 days after injection of Ts1 cells or TsF1 and are specific in suppressing the paracoccidioidal DTH response. In addition, the second-order suppressor cells are T cells with an L3T4- Lyt-2+ I-J+ phenotype and are effective in suppressing only the efferent limb of the P. brasiliensis DTH response. On the basis of the characteristics defined in this study, the paracoccidioidal second-order suppressor cells are equivalent to the Ts2 cells described for other antigen-specific suppressor-cell pathways. Thus, the suppressive circuit induced by Pb.Ag is similar to the suppressor-cell pathways that regulate the DTH responses to azobenzenearsonate, 4-hydroxy-3-nitrophenyl acetyl, lysozyme, and Cryptococcus neoformans antigen. We propose that such a suppressor-cell circuit as defined here with the murine model could be responsible for the depressed cell-mediated immune responses observed in paracoccidioidomycosis patients who have antigen circulating in their sera.

Induction of immunosuppressive B-lymphocytes with components of Candida albicans.

Infections with Candida albicans are associated with a depressed immune response. The immunological profile present during candidiasis is extremely complex. Certain individuals with a congenital defect in the development of a normal cellular immune system are frequently the subject of clinical Candida disease involving mucocutaneous tissues (reviewed in 1). On the other hand, disseminated candidiasis is frequently encountered in individuals suffering with polymorphonuclear leukocyte function such as chronic granulomatous disease, myeloperoxidase deficiency, or Chediak-Higashi Syndrome (2,3,4). Individuals who manifest both mucocutaneous and disseminated forms of candidiasis are rare. The mode of resistance against these two forms of candidiasis presents a paradox since immune mechanisms effective in the first case apparently do not operate in the other.KeywordsCandida AlbicansChronic Granulomatous DiseaseSuppressor CellChronic Mucocutaneous CandidiasisChronic Mucocutaneous CandidiasisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Development of autoimmunity in MRL/lpr mice and the effects of drugs on this murine disease.

MRL/lpr mice spontaneously develop a systemic Lupus erythematosus (SLE)-like disease with a wide range of clinical and serological characteristics that mimic not only human SLE but other autoimmune disorders. such as Sjögren's syndrome, and rheumatoid arthritis (RA). Unlike other murine SLE-like disorders, these mice have circulating rheumatoid factor (RF) and develop histological changes in their joints. Therapy of this disease with cyclophosphamide (CY), cyclosporin A, prednisolone, or leflunomide (HWA 486) resulted in very differing effects. Treating these mice with HWA 486 or cyclophosphamide (CY) resulted in a decrease in the amount of autoantibodies, and immune complex deposits on the glomeruli. HWA 486 therapy led to restoration of the depressed immune response of MRL/lpr mice. In the established disease, prednisolone (Pr), cyclosporin A (CSA), and HWA 486 could inhibit the proteinuria and return the urine-protein values to normal levels, but, unlike HWA 486, neither PR nor CSA could extend the longevity of these animals. The MRL/lpr mouse should prove to be very useful as a model for SLE, RA, and for discovering novel drugs to combat such disorders.

Effects of levamisole on experimental infections by Plasmodium berghei in mice.

Levamisole (phenylimidothiazol), considered a strong immunostimulant, when administered to healthy Swiss mice did not cause a significant increase in -the weight of their thymus, liver and spleen, even though the drug was used at different times before removing such organs. High doses ofdrug used in the 4-day prophylactic scheme had no antimalarial effect. However, when given to malaria infected mice 24 hours before, at the same time, and 24 hours after the inoculation of a chloroquine-sensitive or a chloroquine-resistant strain of Plasmodium berghei small doses of the drug induced a somewhat decreased parasitemia, the dose of 1 mg/kg body weight before the inoculum being the best scheme. The mortality rates by malaria in the levamisole treated groups were also delayed although all mice finally died. The data suggest that levamisole may display a stimulant effect on the depressed immune response caused by malaria.

Critical Vitamin Supplementation of Broiler Diets High in Alfalfa Juice Protein

Three trials were conducted to identify the critical vitamins in the diets of broiler-strain chicks fed alfalfa juice protein concentrate (AJPC) corn-soy diets from 0 to 3 wk of age. Vitamin supplements were added to AJPC diets. Diets were formulated to contain, parts 30/121, 40/128, 50/135, and 60/142 parts AJPC/parts total diet. Parts were used to permit useage of wet materials and still maintain about 90% dry matter. All diets were formulated to contain 20% crude protein, .93% total sulfur-containing amino acids, and 2,940 kcal metabolizable energy/kg diet. Propionic acid was added at .2% to all diets. Feeds were refrigerated (7 C) and fed out daily.The addition of choline, riboflavin, vitamin B12, vitamin A or E, folic acid, or biotin did not increase weight gains. Addition of 3 mg/kg vitamin B6 completely overcame the growth depression caused by the 50-parts AJPC diet and significant (P<.05) growth increases (13 to 29%) were achieved with vitamin-B6 supplementation to the 60-parts AJPC diet. Depressed immune responses were completely prevented by the addition of 3 mg/kg of vitamin B6. The significant (P<.05) increases in leg deformities observed in birds fed the 60-parts AJPC diet were also brought back to more typical values in birds fed the diet supplemented with 3 mg/kg vitamin B6. Vitamin K supplementation (.53 mg/kg) to the 60-parts AJPC diet resulted in significant decreases from 15 min in blood clotting times to 3 to 5 min. Vitamin B12 addition to the 40-parts AJPC diet resulted in a moderate but significant (p<.05) increase in antibody response to sheep red blood cells (SRBC). The results of this study show that feeding AJPC at levels of 50 parts/135 parts diet and above resulted in depressed growth, decreased antibody responses to SRBC, and increased blood clotting times, all of which can be prevented by specific vitamin supplementation. Vitamins B6 and K are crucial in surmounting the toxic effects of saponin found in high AJPC diets.

Activation of immunoregulatory lymphocytes obtained from patients with malignant gliomas

The responsiveness of T cells and their subsets (T-helper cells and T-suppressor cells) obtained from patients with malignant gliomas was evaluated in an effort to further define the mechanism of their impaired host immunocompetence. This study demonstrates that peripheral blood lymphocytes obtained from these patients have impaired responsiveness to a variety of mitogens including phytohemagglutinin, concanavalin A, pokeweed mitogen, and anti-T3 monoclonal antibody. The impaired lymphocyte responsiveness does not result from the inability of these cells to express receptors for a specific mitogen or antibody. The mitogenic responsiveness of purified T cells is markedly reduced when compared to values obtained from control subjects. Therefore, the decreased T cell reactivity of patients with malignant gliomas does not result simply from a diminution in the absolute number of potentially responding lymphocytes. The mitogen reactivity of the T cell subsets, CD4+ helper cells, and CD8+ cytotoxic/suppressor cells was also investigated. These results demonstrate that the responsiveness of the CD4+ T-helper cell subset obtained from these patients is consistently diminished as compared to control values. In contrast, the reactivity of the CD8+ T cell subset was not nearly as dramatically impaired. Thus, these results indicate that the proliferative defect observed in T cells obtained from patients is located predominantly in the T-helper cell subset. Functional deficiencies in this important subpopulation of T lymphocytes may explain, in part, the presence of depressed immune responsiveness in patients with malignant glial tumors.

Langerhans' Cells in Paracoccidioidomycosis

Langerhans' cells (LCs) appear to be altered in diseases that express a depressed cellular immune response. We measured the density of LCs in the skin of patients with the disseminated form of paracoccidioidomycosis. The study was performed using adenosine triphosphatase staining of epidermal sheets. Sixteen patients with paracoccidioidomycosis were evaluated. They had a highly significant reduction in LCs (LCs, 323 +/- 135/mm2) when compared with the number (LCs, 689 +/- 204/mm2) found in the control subjects. Morphological alterations of these cells were noted in patients with low numbers of LCs. These findings may reflect the depressed cellular immunity secondary to the infection with Paracoccidioides brasiliensis.

Lymphocyte subpopulations and lymphocyte reactivity in chronic cigarette smokers.

Cigarette smoke has been implicated as an important risk factor in the development of respiratory disease in smokers. It has been suggested that smoke-induced changes in the immune response may be related to the susceptibility of smokers to respiratory tract infections1). Smokers have been shown to have elevated leukocyte, lymphocyte and T cell counts2, 3), depressed neutrophil chemotactic activity4, 5) and decreased immunoglobulin levels6). Several investigations indicate depressed cellular immune response in small animals following chronic exposure to tobacco smokes7, 8). In humans, an increase in lymphocyte count and decreased natural killer cell activity have been observed in smokers5, 9-11).In the present study, lymphocyte subpopulations and lymphocyte reactivity in peripheral blood were studied in smokers with various smoking habits.

Transient immune deficiency in patients with acute Epstein-Barr virus infection

To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage φX174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying la and T8 (CD8) phenotypes was increased and the T helper/suppressor ( T4 T8 ) ratio was decreased (<1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage φX174 both in vivo and in vitro, In vitro coculture experiments indicated that the la + suppressor T cells could inhibit antibody production and isotype switch. Removal of T8 + lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infections mononucleosis.

Defective interleukin 2 production and responsiveness in human pulmonary tuberculosis.

Patients with newly diagnosed, pulmonary tuberculosis had a tuberculin-specific defect in IL-2 production. Mean PPD-induced IL-2 activity was 81.2% lower in patients as compared with healthy tuberculin reactors. PPD-induced expression of T cell IL-2 receptors was 5.9 times less in peripheral blood mononuclear cells of patients with tuberculosis as compared with healthy tuberculin reactors. Furthermore, purified IL-2 failed to correct PPD-induced blastogenesis in patients. Suppression by adherent cells was operative in one group of patients; adherent cell depletion increased their T cell production of IL-2 7.2-fold. A second group of patients with low IL-2 production did not have suppressor adherent cells and were clinically distinct, with more extensive disease on chest x ray. The basis for low IL-2 production in such individuals is unknown. Disordered regulation of IL-2 metabolism may be a key feature in the depressed cellular immune response of tuberculosis.

Orthodontic care for medically compromised patients: possibilities and limitations

Medically compromised children and adults are increasingly likely to seek orthodontic care as improved medical management creates more long-term survivors. For the majority, treatment of orthodontic problems is feasible, but special precautions usually are required. These include medical consultation to establish the patient's prognosis, maintaining a current knowledge of drug therapy, and modifications in office procedures. Patients with a history of multiple transfusions should be presumed to be hepatitis carriers until proved not to be, and special precautions to protect office staff members and other patients should be taken. Decreased resistance to infection is a common complicating factor in medically compromised patients. Dentists must therefore avoid mucosal irritation and carefully monitor periodontal health. The practitioner should be alert to side effects of drug treatment such as xerostomia and depressed immune response, and be aware of the particular features of the underlying disease. Bleeding disorders, which can be managed by replacement of missing clotting factors, do not contraindicate orthognathic surgery. The major contraindication is poor anesthetic risk, which almost always is true for patients having sickle cell anemia because of poor blood oxygen saturation. Because orthodontic treatment can provide positive benefits, it should not be withheld solely because of the presence of a serious medical problem. With appropriate management, successful orthodontic treatment can be done for most patients.

Dinitrochlorbenzene (DNCB) treatment of viral warts. A 5-year follow-up study

A series of 43 patients with therapy-resistant viral warts of long-duration were treated with dinitrochlorbenzene (DNCB). Of the 37 patients, who completed the treatment, 19 were cured, including five of seven patients with hyperkeratotic tumor-like warts. The majority of the patients showed a depressed cell-mediated immune response. 25 patients were reexamined 5 years later and 8 additional patients answered on inquiry. Six (18%) of these patients had warts. Eight of the 21 primarily tuberculin-negative patients had developed immunity to tuberculin, and none of them had warts. Five of the 6 patients with warts were still tuberculin-negative. The reaction to DNCB had reverted to negative in 17 (68%) out of 25 tested patients and in the majority of the remaining cases a weak reaction only was seen. The study does not tell if the cure is a consequence of the DNCB treatment or a function of time. However, it shows that cure is associated with normalization of the cell-mediated immune response. The DNCB hypersensitivity seemed to disappear with time and late complications were not documented.

Management of Thermal Injuries in Large Animals

The pathophysiology and histopathology of thermal burns in large animals is very similar to that in humans. Burns are classified as first degree, superficial and deep second degree, third degree, and fourth degree, depending upon the depth of thermal injury. Most severe burns will produce a local and a systemic response--both of which must be properly treated to increase the patient's chances for survival. The systemic response is mainly characterized by hypovolemia, fluid and electrolyte loss, protein loss, pulmonary edema, increased caloric requirements, and depressed immune responses. The local response is one of inflammation, vasospasm fluid accumulation, and electrolyte shifts depending upon the extent of the thermal injury. In all burn cases, the total patient should be evaluated. There is a tendency to focus on the wound, and systemic problems may be overlooked. In many cases, the thermal wound cannot be accurately evaluated for a few days, especially in large animals. An attempt should be made to estimate the depth of the burn, because treatment will vary accordingly. The treatment method must consider several problems. These include evaporative fluid and electrolyte loss, protection against mechanical injury, prevention of bacterial invasion and infection, maintenance of body temperature, and removal of nonviable tissue while leaving viable germinal tissue for healing. Thermal injuries in large animals present several additional problems. Many burns in large animals involve a large surface area, which increases the fluid, electrolyte, and caloric losses. Because most veterinary hospitals are not equipped to control the patient's surroundings, extensive bacterial contamination of the burn is of major concern. Patient restraint must also be a consideration to prevent further injury of the healing wound. Many patients are pruritic, and proper measures must be taken to prevent self-mutilation. There is also a lack of technically trained personnel to monitor and properly treat burn patients.

Inhibition of Experimentally Induced Autoimmunity in Rats by Biotin Deficiency

Lewis rats were maintained on diets which provided either an adequate or deficient concentration of biotin. Biotin deficiency produced a marked reduction in thymus size and cellularity, a depressed immune response to sheep erythrocytes and prevented the development of experimental allergic encephalomyelitis following immunization with guinea pig myelin basic protein. Total T cells, T-helper and T-suppressor cells were quantitatively the same in the spleens of rats fed biotin-adequate or deficient diets. By using an adoptive lymphocyte transfer procedure, it was determined that the afferent immune response to myelin basic protein was impaired in biotin deficiency. These results indicate that experimentally induced autoimmune disease is susceptible to the nutritional influence of dietary biotin.

Age and Immune Response to a Surgical Stress

• We studied the effects of age and a relatively standardized stress (elective inguinal herniorrhaphy) on immune response. The patients included 20 men, ten at least 60 years old and ten younger, who were free of infection and illness and had not had prior surgery. Immune responses were measured one day before and five and 30 days after operation. We determined immunoglobulin levels, performed three delayed-hypersensitivity skin tests and a test for neutrophil chemotaxis, and measured lymphocyte responses to autologous cells, phytohemagglutinin-P (PHA), concanavalin A (Con A), and pokeweed. We also studied responses in 40 controls matched for age and sex. The responses to PHA and Con A were significantly lower in older patients than in controls at five days after operation; responses to Con A were still significantly lower at 30 days. Morbidity correlated with depressed immune responses in both age groups, even when there was no difference between older and younger patients. (Arch Surg1983;118:405-409)

Depressed immune response in burn patients

Depressed immune response in burn patients