Marc E. Weksler

Impaired Lymphocyte Function in Aged Humans

The response of lymphocytes from young and old persons to phytohemagglutinin, pokeweed mitogen, or allogeneic lymphocytes has been measured. Lymphocytes from old persons incorporated significantly less tritiated thymidine as compared with lymphocytes from young persons when cultured with plant mitogens or allogeneic cells. The difference in observed lymphocyte reactivity could not be attributed to differences in culture conditions required for maximal transformation of lymphocytes from old or young subjects. The same percentage of thymus-derived and bone marrow-derived lymphocytes was found in the blood from old and young persons. The relationship of these findings to the decline of immunologic competence with age is discussed.

18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease.

Intravenous immunoglobulin (IVIg) has been proposed as a potential agent for Alzheimers disease (AD) immunotherapy because it contains antibodies against beta-amyloid (Abeta). We carried out an open label dose-ranging study in 8 mild AD patients in which IVIg was added to approved AD therapies for 6 months, discontinued, and then resumed for another 9 months. Infusions were generally well-tolerated. Anti-Abeta antibodies in the serum from AD patients increased in proportion to IVIg dose and had a shorter half-life than anti-hepatitis antibodies and total IgG. Plasma Abeta levels increased transiently after each infusion. Cerebrospinal fluid Abeta decreased significantly at 6 months, returned to baseline after washout and decreased again after IVIg was re-administered for an additional 9 months. Mini-mental state scores increased an average of 2.5 points after 6 months, returned to baseline during washout and remained stable during subsequent IVIg treatment. Our findings confirm and extend those obtained by Dodel et al. [Dodel, R.C., Du, Y., Depboylu, C., Hampel, H., Frolich, L., Haag, A., Hemmeter, U., Paulsen, S., Teipel, S.J., Brettschneider, S., Spottke, A., Nolker, C., Moller, H.J., Wei, X., Farlow, M., Sommer, N., Oertel, W.H., 2004. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimers disease. J. Neurol. Neurosurg. Psychiatry 75, 1472-1474] from a 6-month trial of IVIg in 5 AD patients and justify further studies of IVIg for treatment of AD.

Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals.

Active immunization with the human amyloid peptide (Abeta42) or passive immunization with anti-Abeta42 antibodies protects mice that express a mutant human amyloid precursor protein (APP) transgene from cerebral amyloid deposits. If anti-Abeta42 antibodies protect APP-transgenic mice, a model of Alzheimers disease (AD), a high titer of anti-Abeta42 antibodies may protect humans from AD. The titer of anti-Abeta42 antibodies in serum from individuals with and without late onset AD was measured using an ELISA. The titer of Ig (IgM, IgG and IgA) and IgG anti-Abeta42 peptide antibodies was significantly higher in serum from elderly controls than AD patients. Furthermore, IgG but not Ig anti-Abeta42 antibodies distinguished sera from AD patients and elderly controls that did not have the apolipoprotein E4 allele. The low titer of anti-Abeta42 antibodies in AD patients does not reflect the well-established, age-associated defect in the antibody response to most protein antigens, as there was no positive correlation between the serum titer of anti-Abeta42 antibodies and anti-influenza hemagglutinin antibodies induced by influenza vaccine in elderly humans. The lower titer of serum anti-Abeta42 peptide antibodies in AD patients may reflect the reported specific impairment of helper T cell activity for B cells that produce anti-amyloid-beta42 peptide antibodies in APP-transgenic mice.

The Effect of Age on the B-Cell Repertoire

The antibody repertoire changes with age. This change reflects, in part, the age-associated impairment in the production of a diverse population of naive B cells in the bone marrow and, in part, by the decreased diversification of B cells in the germinal center where affinity maturation and isotype switching takes place. B cell number is strictly regulated and despite the decreased output of B cells by the bone marrow does not decline during aging. Self-renewal of peripheral B cells is sufficient to assure the stability of peripheral B cell number. However, when B cell production is stressed as, for example, following drug-induced lymphopenia, the rate of recovery of B cell number as well as of B cell diversity is compromised in old compared to young mice. Finally, aging is associated with the appearance of B cell clonal expansions which not only limit the diversity of the B cell repertoire but very likely give rise to monoclonal serum immunoglobulins and B cell neoplasms.

Changes in the B-cell repertoire with age

Changes in the B-cell repertoire during aging include a shift in antibody specificities from foreign to autologous antigens associated with a decline in the activity of conventional B2 compared to B1 lymphocytes. The age-associated increase in B1 lymphocyte number and activity contribute to the increased serum concentration of autoantibodies and the B-cell clonal expansions that develop with age. Aging is also associated with a decreased diversity of the antibody response reflected in the preferential loss of IgG and high affinity antibodies following immunization with a foreign antigen. Many of these changes can be traced to an impaired capacity of T cells to support isotype switching and somatic mutation in the periphery and the generation of a diverse B-cell repertoire from bone marrow B-cell precursors.

Effect of age on humoral immunity, selection of the B-cell repertoire and B-cell development

Summary: The age‐associated changes in humoral Immunity affect the quality more than the quality of the antibody response. Changes in the quality of the antibody response with age include shifts in antibody specificities from foreign to autoantigens. in antibody isotypes from IgG to IgM, in antibody affinities from HIGH to low and in the antibody idiotypic repertoire. These changes can be traced to an impaired capacity of T cells to facilitate: (a) the maturation of B cells respect to isotype and affinity maturation in the periphery and (b) the development of a diverse B‐cell repertoire from precursors within the bone marrow. In contrast, there is no evidence that the amount of immunoglobulin produced before or after immunization diminishes with age. Nonetheless, the impaired responses of the elderly to most vaccines and the greater susceptibility of the elderly to infections has fostered a view that immune senescence leads to a state of immune deficiency. However, it is more precise to describe immune senescence as leading to a state of immune dysregulation. The dysregulation of the humoral immunity is manifested by a shift from adaptive humoral Immunity, characterized by the production of a highly specific, high‐affinity, IgG antibody response to foreign antigens, to a process of natural antibody‐mediated immunity, dominated by low‐affinity, polyreactive, IgM antibodies which react with autoantigens, Age‐associated T‐cell impairments appear to be the basis for the shift from adaptive to natural humoral immunity and their reversal should permit the restoration of an adaptive antibody response in the elderly.

The Autologous Mixed-Lymphocyte Reaction

Publisher Summary It had been suggested that the autologous mixed-lymphocyte reaction (MLR) might result from perturbations of the responding or stimulating cells during cell fractionation or exposure to foreign sera in culture. The autologous MLR is regarded as a good model for the cooperative interaction between cells involved in the immune response. The lymphocytes that recognize autologous MHC determinants are known to play a crucial role in the regulation of the immune response. The genetic restriction required for cell cooperation among lymphocyte subpopulations and mononuclear cells involves the recognition of HC gene products. These determinants, specified by the HLA-D locus also stimulate the autologous MLR in humans. The discovery that immunological tolerance could be induced by administering foreign antigen to fetal or neonatal animals suggested a mechanism to explain the failure of the immune system to react to autologous antigens. Self-tolerance, established during the ontogeny of the immune system, might preclude immune reactions to autologous antigens. In addition to cell recognition of autologous MHC determinants, regulatory products of T and B lymphocytes react with determinants on autologous cells. Thus, factors produced by suppressor T lymphocytes act only on cells that share I-region determinants with the suppressor T lymphocytes. Auto-anti-idiotypic antibody recognizes surface determinants on autologous B lymphocytes. The impaired autologous MLR observed in patients with diseases associated with abnormal immunological regulation lends additional support for an immunoregulatory role of the autologous MLR. Immune disturbances have been documented in systemic lupus erythematosus, infectious mononucleosis, multiple sclerosis, aging, Sjogrens syndrome, chronic lymphocytic leukemia, and Hodgkins disease. The autologous MLR is altered in each of these states..

Immunological studies of aging: Normal B-cell repertoire in aged mice: Studies at a clonal level

As previously reported, old mice produce lower avidity plaque-forming cells (PFC) after immunization with 2,4,6-trinitrophenyl-Ficoll (TNP-F) than do young mice. However, if spleen cells from TNP-F-immunized old mice are incubated with hapten to elute auto-anti-idiotype antibody then high avidity PFC, comparable to those in young mice, are detected. To further evaluate the effect of age on the B-cell repertoire anti-2,4,6-trinitrophenyl-bovine gamma globulin (TNP-BGG) hybridomas were prepared from young (6 to 8 weeks old) and old (18 to 24 months old) mice which had been primed and boosted with TNP-BGG. The monoclonal antibodies (MoAbs) were TNP-specific. Spleens from old and young mice were comparable with respect to the incidence of immunoglobulin-secreting hybridomas obtained, the incidence of TNP-BGG-specific hybridomas obtained, and the isotype distribution of the anti-TNP-BGG hybridomas. The avidities for TNP-BGG of the IgG1 anti-TNP-BGG MoAbs obtained from old and young donors were also comparable. The overall results thus suggest that old and young mice have similar B-cell repertoires and that differences in the antibodies produced are due to regulatory influences.

The Cellular Basis of the Impaired Autologous Mixed Lymphocyte Reaction in Patients with Systemic Lupus Erythematosus

The autologous mixed lymphocyte reaction is impaired in patients with systemic lupus erythematosus. This is because nonthymus-derived (T)-lymphocyte preparations from such patients do not stimulate autologous T-lymphocyte proliferation normally. This defect may explain the impaired generation of suppressor activity in systemic lupus erythematosus and thereby the occurrence of autoantibodies in this disease.

Relation of chronic disease and immune response to influenza vaccine in the elderly

The ability of elderly patients to mount an adequate immune response to influenza vaccine has been debated. We studied the serum haemagglutination inhibition (HI) antibody response in elderly persons to determine whether different degrees of chronic illness were a critical factor in immune response. In autumn 1986, trivalent split virus vaccine was used to immunize 87 healthy ambulatory elderly adults and 53 institutionalized elderly adults. The pre-vaccination health status of the healthy elderly group was significantly better as measured by the incidence of chronic disorders and drug use (p less than 0.02) and by the Chronic Health Evaluation component of the APACHE severity of disease classification (p less than 0.001). No group differences were observed in serum HI antibody after immunization with the trivalent influenza vaccine. However, in 28 patients from each group who received the monovalent A/Taiwan/86(H1N1) vaccine 1 month after the trivalent vaccine, the percentage with a postvaccination HI titre greater than or equal to 40 was 57% (16 of 28) for the healthy elderly vs 7% (2 of 28) for the institutionalized elderly (p = less than 0.001). Geometric mean postvaccination HI titres were 31 and 13, respectively (p = 0.004). We concluded that the institutionalized elderly in our study mounted an inferior immune response against the new heterotypic influenza A/Taiwan strain when compared to healthy elderly adults. The Chronic Health Evaluation score may be an effective predictor of a poor immune response to new influenza vaccine strains in the elderly. Increasing age per se and lack of a history of prior influenza immunization did not adversely affect the development of protective levels of serum antibody.(ABSTRACT TRUNCATED AT 250 WORDS)