Children with Chronic Suppurative Lung Disease Have a Reduced Capacity to Synthesize Interferon-Gamma In Vitro in Response to Non-Typeable Haemophilus influenzae

Chronic suppurative lung disease (CSLD) is characterized by the presence of a chronic wet or productive cough and recurrent lower respiratory infections. The aim of this study was to identify features of innate, cell-mediated and humoral immunity that may increase susceptibility to respiratory infections in children with CSLD. Because non-typeable Haemophilus influenzae (NTHi) is commonly isolated from the airways in CSLD, we examined immune responses to this organism in 80 age-stratified children with CSLD and compared their responses with 51 healthy control children. Cytokines involved in the generation and control of inflammation (IFN-γ, IL-13, IL-5, IL-10 at 72 hours and TNFα, IL-6, IL-10 at 24 hours) were measured in peripheral blood mononuclear cells challenged in vitro with live NTHi. We also measured circulating IgG subclass antibodies (IgG₁ and IgG₄) to two H. influenzae outer membrane proteins, P4 and P6. The most notable finding was that PBMC from children with CSLD produced significantly less IFN-γ in response to NTHi than healthy control children whereas mitogen-induced IFN-γ production was similar in both groups. Overall there were minor differences in innate and humoral immune responses between CSLD and control children. This study demonstrates that children with chronic suppurative lung disease have an altered systemic cell-mediated immune response to NTHi in vitro. This deficient IFN-γ response may contribute to increased susceptibility to NTHi infections and the pathogenesis of CSLD in children.     

Cell-mediated immune responses in recurrent herpesvirus infections. I. Lymphocyte proliferation assay.

Studies in immunosuppressed and immunodeficient patients indicate that the cell-mediated immune response appears to be responsible for controlling reactivated herpesvirus infections. In this study, the various parameters of a herpesvirus (types 1 and 2) antigen specific lymphocyte proliferation assay were optimized and used to evaluate individuals with clinical, recurrent HSV-1 and HSV-2 infections. Normal individuals with neutralizing antibody to HSV-1 or HSV-2 responded to virus antigen in culture as well as individuals with recurrent disease. Normal individuals without neutralizing antibody responded with a significantly lower response. Specificity of the lymphocyte proliferation assay was observed most strikingly in normal individuals with a rare HSV-1 infection during the vesicular eruption. Specificity was also observed by determining the ratio of the response to HSV-1 as compared to the response to HSV-2. Evaluated in this manner, individuals with recurrent HSV-1 infections had significantly higher ratios than individuals with HSV-2 infections and vice versa. Data from individuals with recurrent disease was compared to that of normal individuals to determine whether the former demonstrated a specific alteration in this response. Individuals with recurrent disease were found to have higher neutralizing antibody titers than normals. The neutralizing antibody titers in normal individuals correlated well with the lymphocyte proliferation assay results, whereas a similar evaluation in individuals with recurrent disease gave a negative correlation. The ratio of HSV-1 response/HSV-2 response also demonstrated a suppressed response in recurrent infections to the homologous virus during active disease, which disappeared when the individual was convalescent. These studies indicate that individuals with recurrent HSV infections have virus antigen specific alterations of their cell-mediated immune response, which can be associated with their disease.     

Immunoresponsiveness in Ulcerative Colitis and Crohn's Disease—Effect of Colectomy and Suppression of Disease Activity

We evaluated the effect of medically induced symptomatic disease improvement on in vitro tests of cell-mediated immune responses in 33 patients with Crohn''s disease. When results obtained in 17 patients with ulcerative colitis were compared with those of 10 patients with ulcerative colitis who had undergone a colectomy, no significant correlation was detected between individual clinical and laboratory variables or the Crohn''s disease activity index and in vitro tests of cell-mediated immunity. A different pattern emerged from the longitudinal tests of cell-mediated immunity: when these test results were initially abnormal in patients with Crohn''s disease, clinical improvement as assessed by the Crohn''s disease activity index was associated with normalizing cell-mediated immunity. In contrast, when the test results were initially normal, clinical improvement was not associated with any change in the immune response. Following colectomy in patients with ulcerative colitis, some abnormalities of suppressed immune responses remained, although patients were cured of their disease. Factors other than clinical disease activity may be responsible for the suppressed immunoresponsiveness in some patients with inflammatory bowel disease, and variable changes in cell-mediated immunity occur after both surgical and medical treatment.     

Trypanosoma cruzi infection from the view of CD8+ T cell immunity--an infection model for developing T cell vaccine

Chagas' disease is caused by Trypanosoma cruzi (T. cruzi) which was once prevalent in Central and South America. Although the recent success in Triatoma vector control has made the disease being possibly "extinct" in the near future, the development of effective preventive and therapeutic vaccines is still necessary to prevent the resurgence of the neglected infection. In addition to the importance for containing the disease, T. cruzi infection presents unique features for elucidating hosts' immune responses against intracellular infectious agents. Due to its biological capacity for invading into principally any types of cells and for causing systemic infection which damages particularly muscle and neural cells, T cell immunity is critical for resolving its infection. Although T cell-mediated immune responses have been, so far, extensively investigated in viral and bacterial infections, parasitic infection such as malaria has presented epoch-making discovery in T cell immunity. Recent advances in the analyses of T cell-mediated immune responses against T. cruzi infection now make this infectious disease potentially more suitable for detecting subtle immunological changes in hosts' immune defense upon modifying immune system. The current review focuses on the usefulness of T. cruzi infection as a model for developing effective CD8(+) T cell-mediated vaccine against intracellular infectious agents.     

Measles virus, immune control, and persistence

Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most acute measles deaths are owing to secondary infections that result from a poorly understood measles-induced suppression of immune responses. Young children are also vulnerable to late development of subacute sclerosing panencephalitis, a progressive, uniformly fatal neurologic disease caused by persistent measles virus (MeV) infection. During acute infection, the rash marks the appearance of the adaptive immune response and CD8(+) T cell-mediated clearance of infectious virus. However, after clearance of infectious virus, MeV RNA persists and can be detected in blood, respiratory secretions, urine, and lymphoid tissue for many weeks to months. This prolonged period of virus clearance may help to explain measles immunosuppression and the development of lifelong immunity to re-infection, as well as occasional infection of the nervous system. Once MeV infects neurons, the virus can spread trans-synaptically and the envelope proteins needed to form infectious virus are unnecessary, accumulate mutations, and can establish persistent infection. Identification of the immune mechanisms required for the clearance of MeV RNA from multiple sites will enlighten our understanding of the development of disease owing to persistent infection.     

The rapidly growing mycobacteria: saprophytes and parasites

Rapidly growing mycobacteria are widespread saprophytes, but approximately one-third of identified species are also opportunistic pathogens in humans and animals, associated with skin, soft tissue, bone, and pulmonary infections as well as disseminated disease. Clinical and experimental evidence indicates a major role for the cell-mediated immune response in the pathogenesis of infection.     

The revaccination against diphtheria and tetanus with adsorbed DT-m anatoxin of children having solid tumors in their case histories

Data on the safety and effect of the vaccination of children with solid tumors are presented. As revealed in this study, the injection of adsorbed DT-m toxoid with reduced antigen content at the period of remission does not induce the relapse of the disease and leads to the production of specific antitoxic antibodies on the protective level. The study has shown that complex antitumor treatment does not essentially affect the formation of specific immune response, though prolonged changes in cell-mediated immunity can be observed.     

Persistent measles infection in malnourished children.

Thirty malnourished and 25 well-nourished children were studied six to 31 days after the onset of a measles rash. Evidence of the virus was found in 40% of the malnourished children but in none of the well-nourished controls. Giant cells were found in the nasal secretions of five out of 17 malnourished children and measles antigen was detected in the lymphocytes of eight out of 28. The malnourished children showed depressed cell-mediated immunity to measles and candida antigens and a low response to meningococcal vaccine. Fifteen died from intercurrent infections. Malnutrition was thought to have depressed the immune response in these children, resulting in a severe and prolonged attack of measles. This, in turn, led to further damage to the immune system and more severe malnutrition. Thus these children were made susceptible to intercurrent infection.     

Diagnosis of Immunologic Deficiency in Childhood

A defective host response may be responsible for recurring infections in certain children. Recognition of these defects may be important both therapeutically for the patient and for genetic counseling for the family. Family history, age of onset of illness and type of infecting agents may all point to one or another defect in host resistance.An initial evaluation for suspected immunologic disease may be rapidly accomplished and should include absolute neutrophil and lymphocyte counts, chest X-ray for a thymic shadow, Schick test for functional IgG antibodies and isohemagglutinin titers for functional IgM antibodies. Although serum protein electrophoresis is unreliable for diagnosis of most disorders of circulating antibodies, quantitation of the IgG, IgA and IgM antibody classes is generally available. More extensive studies may be carried out to further define defects in the cell-mediated immune system, in the various complement components, or in the ingestion and killing of bacteria by neutrophils.     

Immune depression--a possible cause of the unfavorable course of pneumonia in chronic alcoholics

In 27 patients, suffering with chronic alcoholism and hospitalized for pulmonary diseases in the Clinic of Pulmonology and Phthisiology, the following immunological characteristics were checked up: the functional activity of polymorphonuclear leukocytes and in 12 patients also that of alveolar macrophages were evaluated on the basis of the study of the phagocytic index and the phagocytic number, myeloperoxidase and the nitro blue tetrazolium test; the levels of serum IgG, IgA and IgM, the titer of the complement, E-rosette-forming cells (active and total) were also evaluated; the deficiency of cell-mediated immune response was determined by means of intradermal tests with the use of P.P.D., phytohemagglutinin, candidin, trichophytin. In all these investigations the depression of the functional activity of polymorphonuclear leukocytes and alveolar macrophages, dysimmunoglobulinemia, the increased level of circulating immune complexes and the suppression of cell-mediated immunity characteristics were revealed in the patients. Frequent infections and the severe course of bacterial and viral infections observed in such patients can be probably attributed to deficient cell-mediated immune response and to disturbances in phagocytosis.     

Lymphocyte transformation in vitro to RII mouse milk antigen among woman with breast disease.

The cell-mediated immune responses of 110 women with benign or malignant breast disease were tested in in vitro lymphocyte transformation assay with an antigen preparation made from RIII mouse milk containing mammary tumor virus. About 50% of patients responded positively to the milk preparation. In contrast, 25% of normal women or women with other gynecological malignancies responded positively to the antigen (P = 0.015). The data demonstrate a similar response pattern among women with malignant or benign breast disease. In addition, a subpopulation of normal women with positive response to this antigen is clearly defined.     

Indoleamine 2,3 dioxygenase and regulation of T cell immunity

Regulation of adaptive immune responses is critically important to allow the adaptive immune system to eradicate infections while causing minimal collateral damage to infected tissues, as well as preventing autoimmune disease mediated by self-reactive lymphocytes. Tumors and pathogens that cause persistent infections can subvert immunoregulatory processes to protect themselves from destruction by T cells, to the detriment of patients. A growing body of evidence supports the hypothesis that specialized subsets of dendritic cells expressing indoleamine 2,3 dioxygenase (IDO), which catalyzes oxidative catabolism of tryptophan, play critical roles in regulation of T cell-mediated immune responses. IDO-dependent T cell suppression by dendritic cells suggests that biochemical changes due to tryptophan catabolism have profound effects on T cell proliferation, differentiation, effector functions, and viability. This has critical implications for immunotherapeutic manipulations designed for patients with cancer and chronic infectious diseases. In this review, I focus on dendritic cells that can express IDO, and which acquire potent T cell regulatory functions as a consequence.     

The role of CD8<Superscript>+</Superscript> T cells in immune responses to colorectal cancer

Cytotoxic T lymphocytes (CTL) are essential effectors of the cell-mediated immune response. The ability of CTL to specifically recognise and lyse malignant cells expressing the relevant surface antigens under optimal in vitro conditions justifies attempts to boost their number and activity through various forms of immunotherapy. Considering the high prevalence of colorectal cancer and poor survival rates for patients with advanced-stage disease, the development of new protocols based on CTL stimulation represents a genuine and promising treatment option. Significant advances in recombinant DNA technology and molecular biology have led to the identification of a number of tumour-associated antigens (TAA). These have served as vaccine constituents and/or stimuli for obtaining CTL used for adoptive immunotherapy after in vitro stimulation and expansion. The present review describes the properties and functions of CTL as effectors of the immune response against tumours, and summarises the known TAA recognised by CTL and the current status of CTL-related immunotherapeutic interventions in colorectal cancer patients.     

Cell-mediated and humoral immune responses to aspermatogenic antigen in experimental allergic orchitis in the guinea-pig

Guinea-pigs were immunized with a defined and highly potent aspermatogenic antigen, G75m, and the occurrence of orchitis was correlated with (1) cell-mediated immune response to G75m, determined by lymph node cell proliferation and by secretion of macrophage migration inhibitory factor (MIF) by peritoneal exudate cells, and (2) humoral antibodies to G75m and to cell surface antigens of guinea-pig testicular cells, by radioimmunometric assays. A consistent temporal relationship between cell-mediated immune responses and disease was found: lymph node cell proliferation was positive by Day 4, followed 3 days later by maximum secretion of MIF, and orchitis lesions were manifest on Day 10. In contrast, maximal IgG antibodies to G75m or to the surface antigens of spermatozoa/testicular cells were detected at a time when cell-mediated immune responses and active testicular lesions had subsided. In individual animals, lymph node cell proliferation increased with severity of orchitis, while MIF secretion by peritoneal cells increased with orchitis only late in the disease. Early in disease, MIF response showed a negative correlation with orchitis. Moreover, peritoneal injection of oil reduced the incidence of early lymph node cell proliferative responses, and delayed the onset of testicular disease. These findings are consistent with competition between different inflammatory sites for recently antigen-activated T lymphocytes. We conclude that (1) the development of orchitis correlates with cell-mediated immune responses to purified aspermatogenic antigens but not with IgG antibody responses, and (2) when the same animal is used to assess different aspects of cellular immunity and autoimmune disease, one study may significantly influence the other.     

Modulation of immune responses following antigen administration by mucosal route

Most microbial infections are either restricted to the mucosal membranes or the etiologic agents needed to transit the mucosa. Thus, it is desirable to stimulate a mucosal response following vaccination, to block both infection and disease development. Attenuated vaccine carriers mimic natural infections, triggering also mucosal responses. Similar results can be achieved by administering antigens with appropriate adjuvants. However, the delivery of antigens per se is not sufficient to engender a protective response. A successful immunization requires the elicitation of an appropriate type of immune response (e.g. antibodies vs. cell-mediated immunity, Th1 vs. Th2 helper pattern). Therefore, a successful vaccination strategy demands the choice of adequate antigens, and their appropriate delivery and/or formulation to promote the required quality of immune response. Different strategies to optimize the immune responses elicited following vaccine administration by the mucosal route are discussed.     

Characterization of the immune status of patients with vaccine-associated poliomyelitis

Specific humoral immunity, total immune status and typing of HLA antigens, class 1, in loci A and B were studied in children with vaccine-associated paralytic poliomyelitis (VAPP). The immune status investigation revealed that changes in the content of serum immunoglobulins were most frequent. Out of 8 examined children, 5 children had IgA deficiency and 1 child had total variable immunodeficiency. In one case disturbances in cell-mediated immunity prevailed. Tissue typing revealed the presence of HLA A2 and B44 in 5 out of 6 examined children, which considerably exceeded their average occurrence among the Belorussian population. In spite of frequent detection of immunological disturbances in VAPP patients, out of 38 serologically examined children 36 (95%) were found to have virus-neutralizing serum antibodies to poliovirus, which was indicative of the capacity of their immune system for response to the administration of vaccine virus. To minimize the risk of VAPP in children and to achieve the goal of poliomyelitis eradication the combined immunization scheme consisting of 1-3 vaccinations with inactivated poliovaccine with subsequent administration of oral vaccine prepared from attenuated Sabin viruses is regarded as most promising.     

Production of migration inhibitory factor (MIF) by human leukocytes following exposure to Epstein-Barr virus.

The ability of Epstein-Barr virus (EBV) to induce a cell-mediated immune response (CMI) in cultures of human leukocytes was investigated. Partially purified EBV, obtained from culture fluids of AV-1 cells, was inactivated by uv-irradiation. Inactivated virus was mixed with peripheral leukocytes from Hodgkin's disease (HD), infectious mononucleosis (IM) and malignant lymphoma patients as well as from normal individuals in an in vitro culture system. Production of migration inhibitory factor (MIF), as measured by guinea pig macrophage migration inhibition (MMI), was utilized as an indicator of CMI response. Significant differences in MIF response were observed subsequent to exposure of the cells to EBV. Leukocytes from patients in each of the disease categories tested exhibited greater MIF production than did those from the normal controls. There were significant differences in MIF production by leukocytes from the malignant and non-malignant disease categories. Serum from each subject was examined for immunoglobulin specific for EBV capsid antigen (anti-VCA). Although the majority of individuals within the disease categories tested had elevated anti-EBV serum titers, no correlation could be made between elevated anti-VCA titer and levels of MIF production.     

Cellular immunecompetence in patients with malignant melanoma

Summary The nonspecific immunecompetence of the peripheral blood lymphocytes of 29 patients with malignant melanoma and one with the benign condition of Riehl's melanosis was tested by means of a local xenogeneic graft-versus-host reaction and the E rosette test. The lymphocytes of 20 normal donors served as controls. Impairment of cellular immunecompetence was found in patients with invasive multiple primaries and those with invasive nodular malignant melanoma. Functional activity of T lymphocytes was normal in most of the patients who had an invasive melanoma with adjacent intraepidermal component of Hutchinson melanotic freckle or superficial spreading. In three cases with superficial spreading in which there had been an impairment of T cell function before removal of the tumor, there was an improvement following surgery. There was a clear correlation between the patient's cell-mediated immune response and the pathological type of the tumor, but not with the depth of invasion. It is suggested that cellular immunecompetence is a valuable parameter in the prognosis and treatment of malignant melanoma and should be measured in all patients with this type of tumor.