Ageing and genetic control of immune responsiveness

Ageing is associated with a progressive decline of immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena [1,2]. Many studies have been focussed on the mechanisms of the immunologic features of ageing. Alterations in cellular components of the immune system rather than in the extracellular milieu seem to account for most of the variations of immune competence in ageing [3].     

Heterogeneity of immune responsiveness in healthy elderly subjects

We studied a group of healthy elderly subjects (satisfying the SENIEUR Protocol admission criteria), chosen as a model of age-associated immune deficiency on the basis of their reduced skin reactivity to recall antigens. Results show that aged subjects, taken as a whole, display impaired T-cell functions: reduced blastogenetic responses to mitogens, IL-2 production, responsiveness to exogenous IL-2, and percentage of Tac positive blasts. However, the age-associated immune defect shows a wide range of impairment, even in a relatively homogeneous group of anergic/hypoergic subjects. In fact, a considerable proportion of our elderly subjects displays responses comparable with those of adult controls. These observations suggest that (a) immune deficiency is not a characteristic of aging per se; (b) cutaneous delayed hypersensitivity is not a criterion sensitive enough to identify people with age-associated immune deficit; and (c) more than one test is required to evaluate T-cell impairment in aging.     

DNA vaccination and the immune responsiveness of neonates

Neonates often respond poorly to conventional vaccines or microbial infections. Immaturity of the immune system has been considered to play a role in this regard. However, accumulating evidence shows that in certain conditions, neonatal inoculation of antigens leads to protective immunity. In the particular case of DNA vaccines administered to neonates, the rule is immunity rather than tolerance. Exceptions to the rule give opportunities to further understand the neonatal responsiveness and the mechanism of DNA vaccination. Due to the very nature of the vaccine vector, inhibition of neonatal DNA vaccination by maternal antibodies may be limited to the humoral immunity.     

Natural haemagglutinins and immune responsiveness in young chicks

Titres of natural haemagglutinins to sheep erythrocytes and of experimentally induced antibodies to Newcastle disease virus (NDV), bovine serum albumin (BSA) and human gammaglobulin (HgG) were determined in White Rock broiler chicks immunised at 28 days of age. There was no relationship between levels of natural haemagglutinins and induced antibody levels or between titres of antibody to NDV and titres of antibody to BSA or HgG. A highly significant correlation (r=0.37) was found between titres of antibody to BSA and to HgG.     

A ''profile'' of immune responsiveness in multiple sclerosis.

An 'immunological profile' of various indices of B-cell function and T-cell function was developed for the 'early' case of multiple sclerosis (MS). This was compared against two groups of controls comprising age and sex-matched healthy subjects, and patients with other disabling neurological diseases (CNS controls) who were matched for age, sex, and type and duration of disability. Some indices of humoral immune responsiveness, such as the induced primary response to monomeric flagellin and the 'resting' levels of antibody to measles and rubella viruses, showed significant augmentation. Cellular immune deficits were attributed to an illness effect per se because (a) cell-mediated immunity was depressed, but only when compared with that of healthy subjects and not when compared with that of the CNS controls, and (b) transformation responses of lymphocytes to viral antigens were inversely related to disability status. The abnormalities in humoral immune responses demonstrable in this study do not provide an explanation for this disease; if there is a relevant 'immunological fault', the nature of this needs to be sought from within the neuraxis rather than from the systemic circulation.     

The effect of diet on immune responsiveness and aging

Immunologic changes which occur during aging include decreased responsiveness to exogenous antigens and increased autoimmune responses. Autoimmune reactions to autologous antigens may interfere with the physiologic function of these antigens and be a factor in the 'wearing out' of tissue during aging. Amelioration of age associated autoimmunity may result in an increased life span. Dietary manipulation has been shown to produce changes in the immune system of experimental animals. Some benefits include a decreased propensity to spontaneous autoimmune disease with a resultant increased life span. Dietary changes may be capable of producing similar beneficial effects in humans.     

Ontogeny of the murine immune system: development of antigen recognition and immune responsiveness

The grafting of a single spleen colony obtained from irradiated mice protected with 12-day fetal liver will reconstitute the lymphopoietic and erythropoietic system of irradiation-deprived syngeneic recipients. Using this experimental model, the early events during the ontogenic development of the immune system were studied in CBA mice. Cells capable of binding radio-iodine labeled S. adelaide polymerized flagellin were first detectable after 18 to 20 days of lymphopoiesis starting from presumably a single stem cell. However, antibody-forming cell production after immunization against the same antigen was not demonstrable until days 19 to 26. The same sequential development of antigen recognition (by rosette formation) followed by immune reactivity was observed for sheep red cell antigens, both events occurring later than those for POL. Our observed requirement for the ontogeny of an antigen-recognition spectrum is compatible with Jerne's theory on the generation of antibody diversity.     

Recent progress in studies on cell-mediated immune responsiveness in insects

Comparative immunologists have been engaged in a search for the origins of cell-mediated immunity for a long time. One group of invertebrates that have been receiving increasing attention has been the insects. These animals not only serve as good experimental models, but are of great interest because of their evolutionary success. Several studies have shown that insects generally respond to particular foreign material by mounting an encapsulation reaction. On a more specific level, insects have also been found to be capable of quickly rejecting integumentary xenografts. A basic enigma however, has been the reported inability of insects to respond to integumentary allografts. Recent work from our lab indicates that if one concentrates on the fate of the soft tissue component of the integument, one can readily demonstrate allograft reactivity in these animals. We have now confirmed this by yet another system which monitors the loss of 3H-thymidine from labeled allo- and autografts. Thus, future studies promise to unravel some long sought after questions concerning the evolution of cellular defense mechanisms.     

In vitro immune responsiveness to vaccinea virus and HLA.

Because several lines of evidence suggest that HLA products might have an important function in the immune response to infectious agents, we studied the possible relation between immune response to vaccinia virus and HLA phenotype in 79 soldiers who received a primary vaccination. A low in vitro response to vaccinia virus was associated with HLA-Cw3 both in 49 subjects tested three to four weeks after vaccination (P less than 0.001) and in the remaining 30 subjects tested five to 11 weeks after vaccination (P = 0.035). Responses to unrelated antigens and phytohemagglutinin of lymphocytes tested before, three to four weeks and five to 11 weeks after vaccination indicated that this association was specific for vaccinia virus and suggested that differences in immune response to vaccinia were reflected in temporarily altered immune responsiveness to unrelated antigens. Our results indicate that HLA-Cw3 or an HLA product associated with Cw3 is involved in the cellular immune response to vaccinia virus.     

Prenatal alcohol exposure selectively suppresses cell-mediated but not humoral immune responsiveness

The present study examined effects of fetal alcohol exposure (FAE) on the ability of peripubertal male and female rats to mount a humoral immune response against T-cell-dependent as well as independent antigens. The appropriate pair-fed (PF) and control (C) cohort rats were included. Serum immunoglobulins (Ig) levels were determined following a primary or secondary immune response. In addition, plasma corticosterone levels were measured in conscious, freely moving FAE, PF and C rats following sensitization with the T-cell-dependent antigen sheep red blood cells (SRBC). The study demonstrates that, in response to primary or secondary immunization, serum Ig levels in FAE rats were not significantly different from those in the PF or C cohorts. On the other hand, a marked reduction in mitogen-induced T-cell proliferative response was observed in FAE male rats in the same age group. Plasma corticosterone concentrations were increased almost four-fold 7 days after the primary immunization with SRBC, but there were no significant differences among the FAE, PF or C groups. Taken together, evidence from in vivo and in vitro studies indicates that FAE is associated with a selective impairment of cell-mediated immune function, including mitogen-induced T-cell proliferation, graft versus host as well as contact sensitization responses, but not of humoral immune function.     

Suppression of immune responsiveness by a submandibular salivary gland factor.

Both tissue extracts prepared from submandibular salivary glands of male mice and epidermal growth factor isolated from these glands depressed the delayed type hypersensitivity response to 2,4-dinitro-1-fluorobenzene in mice. Extirpation of the submandibular salivary glands from male mice did not alter the delayed type hypersensitivity response. The role of salivary gland factors, particularly epidermal growth factor, in influencing the immune response has been discussed.     

Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness

We investigated the impact of cigarette smoke exposure on respiratory immune defense mechanisms. Mice were exposed to two cigarettes daily, 5 d/wk, for 2-4 mo. Tobacco smoke decreased the number of dendritic cells (DCs) in the lung tissue. Furthermore, smoke exposure dramatically reduced the percentage of B7.1-expressing DCs. Because DCs are believed to be indispensable to the initiation of adaptive immune responses, we investigated the impact of cigarette smoke on immune responsiveness toward adenovirus. Mice were exposed to two cigarettes for 2-4 mo and inoculated with 2 x 10(8) pfu of a replication-deficient adenovirus on three occasions, 2 wk apart, during the last month of tobacco smoke exposure. Smoke exposure specifically prevented the expansion and maximal activation of CD4 T cells and reduced the number of both activated CD4 and CD8 T cells. Consequently, smoke exposure shifted the activated CD4:CD8 T cell ratio from 3 to 1.5 when compared with sham exposure. Significant decreases were also observed in serum adenovirus-specific pan IgG, IgG1, and IgG2a immunoglobulin levels, which was associated with diminished viral neutralization capacity. We demonstrate that chronic tobacco smoke exposure impairs the immune response against adenovirus. This may, in part, explain the increased prevalence of viral infections in chronic obstructive pulmonary disease.     

Effect of influenza virus on the immune responsiveness of animals.

Infection of mice with A/Hong Kong/1/68 (H3N2) and A/PR8/34 (H0N1) influenza virus strains resulted in a significant inhibition of the formation of antibody-producing cells in response to administration of sheep erythrocytes and a reduced capacity of spleen cells to induce "graft-versus-host" reaction. The immunosuppression caused by influenza infection was observed for a long period of time post infection (3--6 months). The extent of inhibition of antibody production depended on the dose of virus, route of inoculation, the sequence of infection and immunization and the internal between them. Heat-inactivated virus exerted no immunosuppressive effect.     

A model for personalized in vivo analysis of human immune responsiveness

Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34(+) cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune-mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele-matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (T(regs)), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34(+) cell donor, but the T cell phenotypes were more predominantly "na?ve" than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural T(regs) intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This "personalized immune" mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well.