Koichi Uyemura

Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents

Peripheral blood mononuclear cells (PBMC) of frail elderly nursing home residents had significantly higher PHA-induced interleukin-10 (IL-10) production compared to PBMCs from young control subjects. No correlation was observed between IL-10 production and interleukin-12 (IL-12) p40 production, proliferative response or with the proportion of CD28-negative T cells. To better characterize the host response to a ubiquitous pathogen, the dose response and time-dependent (kinetic) production of IL-10 and IL-12 p40 of PBMC stimulated with Staphylococcus aureus Cowan (SAC) was studied. IL-10 production continued to increase at 48 h, while IL-12 p40 levels declined or remained stable, in both young and elderly subjects. In analyzing how excessive IL-10 production might influence antigen presenting cell functions, IL-12 was markedly inhibited by recombinant IL-10 (rIL-10), while anti-IL-10 enhances IL-12 p40 production in cultures from young controls; but the PBMC cultured from an elderly cohort were not able to generate similar absolute levels of IL-12 p40 even in the presence of anti-IL-10. These preliminary data suggest that there may be both over production of IL-10 in some individuals, as well an an impaired ability to upregulate a T Helper 1 (type 1) reaction. These age-related changes could even be more dramatic at the tissue level and contribute to the impaired delayed type hypersensitivity (DTH) and failed host defense to infection, such as to primary and reactivation tuberculosis.

Host Resistance and Immune Responses in Advanced Age

Immunosenescence results in populating immune tissues with less functional T cells, and perhaps B cells dendritic cells, that do not function well and produce more type 2 cytokines and fewer type 1 cytokines. Impaired immunity, distinct from immunosenescence, correlates more with disease burden than chronologic age. Older adults who have chronic diseases or chronic infections are more susceptible to common infections and have poor vaccine responses. Understanding specific mechanisms and targeting interventions are dependent on research to resolve the relationship between frailty-associated impaired immunity and the role of chronic infection versus immunosenescence in developing impaired immunity.

Comorbidity is a better predictor of impaired immunity than chronological age in older adults.

Objectives: To determine whether high level of comorbidity, measured using a standardized instrument, can predict impaired immunity in older adults.

Immune dysfunction in the elderly and its reversal by antihistamines

The decline in immunity seen in the elderly is a significant contributor to disease burden. This decline has largely been attributed to alterations in T cell immunity and contributes to an overall increased risk and severity of infection in the elderly. A key component of T cell immunity involves antigen presentation, an event where an antigen is processed and presented to specific immune cells for destruction. This event has been found to be crucial to immune function. Recent research has focused on a key antigen presenting cell (APC), the dendritic cell (DC), and changes within its function associated with aging. DCs are considered to be the most professional APCs, and are responsible for the initiation and outcome of effector T cells and their resultant immune response. DCs capture antigens and undergo a maturation process and polarize into either type 1 dendritic cells (DC1) or type 2 dendritic cells (DC2), based upon their ability to favor a T helper1 (Th1) or T helper 2 (Th2) T cell response, respectively. Evidence suggests that in normal healthy adults, a Th1 type response predominates, and in frail elders, a Th2 response predominates. It has been proposed that this change from a predominately Th1 type to a predominate Th2 type response is a possible mechanism for age-associated immune dysfunction. In addition, recent research has focused on how histamine, an inflammatory mediator, promotes a Th2 response. Histamine has also been shown to polarize human DCs into Th2 cell-promoting effector DCs or DC2s. This has been shown to occur via interaction with the H2 receptor. Therefore, we theorize that use of an H2 selective antihistamine will reverse this polarization back to a Th1 type response and therefore improve immune function of the frail elderly.

A Need to Study the Immune Status of Frail Older Adults

The frail older adult subpopulation, which is growing at a rapid rate, contributes significantly to the increasing global healthcare cost [1]. Many frail older adults are immunologically compromised, and, therefore, succumb to common infections in spite of the availability of antibiotics and other therapeutic measures. It is also not known how repeated or recurrent infections affect the progression of the underlying chronic disease. Thus, there is an urgent need to understand the nature of the diminished immune capacity of frail older adults, for it could provide new insight into developing effective intervention modalities. Unfortunately, very little research has been done to describe and elucidate the immune deficits of the frail older adults. In the past, researchers have been discouraged to study this subpopulation because of its complexity in terms of disease category and disease burden. In contrast, much is known of the immune status of the healthy older adult subpopulation, for this subpopulation has been investigated extensively over the past three decades. Thus, it is known that T cell-dependent immune functions decline with age [2], and associated with the decline are structural changes in T cells [3]. However, a review of more than 200 scientific articles that evaluated healthy older adults, who were selected on a set of rigorous criteria as defined by the SENEIUR Protocol [4], showed that the magnitude of decline in T cell-dependent immune functions with age is modest [5], relative to that of the aging mouse model [6]. More recently, Sehl and Yates [7] analyzed changes in various physiologic functions with age from 469 studies involving more than 54,000 healthy and frail older adults. The expansive review included 43 immunologic studies of 372 individuals. They found that the mean annual rate of decline with age in immune functions is greater than that of other physiologic functions that were assessed. The authors concluded that the deterioration in immune function in older adults is due not only to aging, but also the presence of chronic disease. This review also underscores the need to evaluate the immune status of frail older adults with chronic diseases. Recently, the influence of chronic disease on T cell immunity as been investigated [8], using the Cumulative Illness Rating Scale (CIRS) [9]. CIRS is an instrument that measures disease burden in individuals with various chronic diseases, but with no evidence of acute deterioration or infection. The CIRS instrument was originally developed in 1968 and is acknowledged as a user-friendly, comprehensive review of medical problems of 14 organ systems [9]. It is based on a 0 to 4 rating of each organ system. The scale has been validated in older adults living in long-term care facilities and congregate apartments in the community and has demonstrated better validity in predicting healthcare outcomes than functional measures [10]. T cell immunity was based on phytohemagglutinin (PHA)-induced proliferation and production of immunosuppressive interleukin (IL)-10 and immunoenhancing IL-12. The study showed that decrease in T cell proliferation, increase in production of IL-10 and decrease in production of IL-12 are linearly correlated with increase in chronic disease burden (i.e., increased CIRS score), but not with increase in chronologic age, between 51 to 95 years. The demonstration that reduced immunity in older adults is correlated with chronic disease burden, but not with chronologic age, suggests that chronic disease burden markedly enhances the reduction in immunity of older adults caused by biologic aging. Others have suggested chronic infections, caused by especially cytomegalovirus, and also by Helicobacter pylori, Mycobacterium tuberculosis, Chlamydia pneumoniae, Herpes viruses, Epstein-Barr virus, and Hepatitis viruses, could play a role on progression of chronic disease, especially atherosclerosis, and impaired immunity [11-15]. While CIRS does not directly address prior viral infections, if these infections do impact on progression of disease it would be predicted that there would be a correlation between CIRS and evidence of chronic infection. Chronic infections, increased levels of inflammatory mediators, disease progression and frailty have a very complex association, and, furthermore, an unclear temporal relationship. Therefore, at this stage of progress, it would be appropriate and timely, to study the immune status of frail older adults using an instrument, such as the CIRS, to categorize frail older adults according to specific chronic disease and disease burden. The immune status of frail older adults in each category could then be assessed, and immunosuppressive factors produced by specific disease that are present in the microenvironment of immune cells could be identified and their impact on immunity mitigated. Consequently, the compromised immune status of frail older adults could be boosted to that of healthy older adults, thereby improving their innate and adaptive immunologic defense mechanisms to infections and response to vaccination. This should significantly increase their resistance to infectious and other immunocompromised-related diseases, possibly slow the progression of chronic diseases, and, therefore, contribute to the goal of reducing the global healthcare cost.

γδ T Cells in Leprosy Lesions

Leprosy provides a useful model for understanding immunoregulatory mechanisms in man, since the disease form a spectrum in which the immunologic response of the patient correlates with the clinical and histopathologic classification. Since leprosy is predominantly a disease of skin, it provides an opportunity to study the immune response to infectious pathogens at the site of disease activity. At one end of the spectrum, patients with tuberculoid leprosy have one or several skin lesions in which bacilli can rarely be identified. CD4 + T-lymphocytes predominate in these lesions (12) and respond to Mycobacterium leprae in vitro (11). At the other end of the spectrum, patients with lepromatous leprosy have diffuse infiltration of skin and nerves with bacilli-laden macrophages. CD8 + cells predominate in lepromatous lesions and function as antigen specific T-suppressor cells in vitro (13,14). The CD4+ lymphocytes derived from these lesions are unresponsive to M. leprae in vitro.