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Biomedical subjects

M E Weksler

Publications and source records attributed to M E Weksler.

At least 19 recordsLinked to original sources
PubMed1992

Prothymosin alpha expression occurs during G1 in proliferating B or T lymphocytes.

To gain insight into possible functions for prothymosin alpha in the proliferative cycle of lymphocytes, we examined the kinetics of prothymosin alpha mRNA expression in mitogen stimulated murine lymphocytes. This mRNA increases after mitogen stimulation, peaking in mid G1. This kinetics is compatible with induction of the prothymosin alpha gene by the c-myc protein (Eilers, M., Schirm, S. and Bishop, J.M. (1991) EMBO J., 10, 133-141). Thus, although prothymosin alpha mRNA is found throughout the cell cycle, the elevated expression in G1 may be associated with an increased requirement for prothymosin alpha during the G1/S transition or the S phase of the cell cycle.

Animals↗
PubMed1992

Altered major histocompatibility complex-restricted antigen recognition by T cells from elderly humans.

Positive selection of T cells within the thymus gland leads to major histocompatibility complex (MHC)-restricted recognition of antigen by T lymphocytes. As the thymus gland involutes with age, altered MHC-restricted antigen recognition by T cells from elderly humans would be expected. We have tested this hypothesis by comparing the proliferative response of T cells and T cell clones from aged and young subjects to influenza determinants presented by autologous or allogeneic antigen-presenting cells (APC). Under conditions in which the allogeneic mixed lymphocyte reaction was minimal, T cells from six of seven aged donors but only one of seven young donors were stimulated by influenza vaccine presented by allogeneic APC. More importantly, one-half of the influenza-specific T cell clones derived from aged donors, but none of the clones derived from young donors, were activated by influenza vaccine presented by allogeneic APC. While 80% of the MHC-nonrestricted influenza-specific T cell clones expressed the gamma/delta T cell receptor, 20% of these clones expressed the alpha/beta T cell receptor. Thus, changes in MHC-restricted antigen recognition by T cells and in altered distribution of alpha/beta versus the gamma/delta T cell receptor bearing antigen-specific T cell clones occur with aging.

Adult↗
PubMed1992

Immune senescence: mechanisms and clinical implications.

There are many changes in the immune response with age, most of which can be related to the involution of the thymus gland and alteration of the distribution and function of T lymphocytes. These changes indirectly influence B-cell function, which not only amplifies the immune deficits, but leads to the increased production of autoantibodies and monoclonal immunoglobulins with age. Thus, immune senescence is characterized by both an immune deficiency and an immune dysregulated state.

Aging↗
PubMed1992

The immunogenetics of immune senescence.

Immune senescence is characterized by a dysregulation of the immune system. With respect to humoral immunity, aging is associated with an increased level of many autoantibodies and a decreased antibody response to most foreign antigens. This observation reflects a decreased capacity to activate antibody production by CD5-negative B cells despite a normal or increased capacity to generate antibodies produced by the CD5-positive B cells. A similar dysregulation of cell-mediated immunity is manifested by an altered balance in cytokine production by T cells from old as compared to young subjects. Thus, the production of interleukin-2 (IL-2), IL-3 and granulocyte-macrophage colony-stimulating factor by T cells from old subjects is decreased although the production of IL-4, IL-5 and IL-6 is undiminished or actually increased.

Aged↗
PubMed1992

Host resistance and the immune system.

Elderly persons are more susceptible and vulnerable to many infections compared with young adults. This phenomenon can be attributed to a decline in host defense mechanisms, particularly altered immune function. The effects of aging on T- and B-lymphocyte function; antigen-presenting cells, natural killer cells, and granulocytes; and organ-specific host resistance are discussed in this article.

Aged↗
PubMed1991

"Cross-wiring" of the immune response in old mice: increased autoantibody response despite reduced antibody response to nominal antigen.

Older humans and experimental animals have been repeatedly found to have higher titers of autoantibodies than do younger individuals despite the impaired responses of older individuals to foreign antigens. The studies reported here were designed to examine the relationship between these two age-related changes in antibody responses. Antibody response to foreign antigen was measured concurrently with autoantibody response in the same mice. Old mice (18-24 months old) had decreased responses to foreign antigens and increased responses to bromelain-treated syngeneic erythrocytes, compared to young mice (2 months old). In vitro mixing experiments were consistent with the possibility that suppressor cell activity in spleen cells from old mice reduce the antibody response to foreign antigen but not to autologous antigen. The results support an emerging view that age-associated changes in immune responses are the result of dysregulation rather than exhaustion of the immune system.

Aging↗
PubMed1990

Decreased steady state c-myc mRNA in activated T cell cultures from old humans is caused by a smaller proportion of T cells that transcribe the c-myc gene.

The proliferative response of T cells is known to decrease with age of the T cell donor. We now report that this proliferative defect affects both major subsets (CD4+, CD8- and CD4-, CD8+) of peripheral T cells from old humans. Furthermore, this proliferative defect can be detected within the first hours after addition of mitogen by a reduction in the steady state levels of c-myc mRNA in T cell cultures from old donors. Lymphocytes from old humans cultured with PHA have less than 50% of the level of c-myc message than do such cultures from young donors. Nuclear run-on assays suggest that the decreased steady state level of c-myc mRNA in cultures from old donors is caused by reduced transcription of the c-myc gene in T cells from old donors. The age-associated defect in transcription of the c-myc gene affects the second exon to a greater extent than the first, noncoding exon. Individual T lymphocytes from old donors that do express c-myc message, detected by in situ hybridization, have the same intracellular level of c-myc message as T lymphocytes from young donors. These data add additional support for the hypothesis that the proliferative defect of T lymphocytes from old humans is caused by the smaller fraction of T cells from old as compared with young humans that can be activated by mitogens to enter the G1 phase of the cell cycle.

Aging↗
PubMed1990

Defective expression of high affinity IL-2 receptors on activated T cells from aged humans.

The proliferative response of T cells from aged humans to a number of mitogens is significantly reduced. We report here that there is a decrease in high affinity IL-2 receptor (IL-2R) expression on activated T cells from aged humans. Scatchard analysis of the binding of [125I]IL-2 demonstrates fewer high affinity IL-2 binding sites. Autoradiographic techniques demonstrate that this results from there being fewer activated T cells from old as compared to young donors that express high affinity IL-2R. However, T cells from old donors that do not express high affinity IL-2 binding sites express both the IL-2 binding 55 and 75 kd chains. Thus, although the two IL-2 binding peptides are expressed on activated T cells from old donors, expression of the high affinity IL-2R is reduced. This may explain the decreased ability of T cells from old donors to respond to IL-2. The impaired ability of activated T cells from old donors to express high affinity IL-2R while expressing the 55 and 75 kd chains may provide insights into the mechanisms of IL-2 interactions with its receptor.

Adult↗
PubMed1990

Cellular basis for the age-associated increase in autoimmune reactions.

The mechanisms that lead to the increased expression of autoantibodies with age are poorly understood. We have studied the number, size, and density of spleen and peritoneal cells from young and old BALB/c and C57BL/6 mice as well as the frequency of clonal precursors for antibodies to mouse erythrocytes, thyroglobulin, and IgG in these lymphoid preparations. Old mice have a 6-fold increase in the number of resident peritoneal cells and a 2-fold increase in the absolute number of Ly1-bearing B cells in this population. Furthermore, old mice have twice as many large, low density splenic B cells as young mice. The frequencies of B cell clonal precursors for anti-BrMRBC and anti-thyroglobulin antibody-forming cells in old mice were 3-10 times greater than in young mice. In the same cultures, however, no increase in the frequencies of B cell clonal precursors for anti-IgG or anti-DNA antibody forming cells was detected in old compared to young mice. These findings and other data suggest that there are at least two families of B cell autoantibody precursors, one including anti-BrMRBC and anti-thyroglobulin autoantibodies, the other including anti-IgG and anti-DNA antibodies. Studies of the differential regulation of these two families of autoantibody precursors might contribute to a greater understanding of autoimmune phenomena in age and disease.

Aging↗
PubMed1990

Immunobiology of aging and cancer.

Although the incidence of neoplasms is increased in the elderly, some tumors appear to grow more slowly in old as compared to young patients. We have used the B16 melanoma to explore the relationship between age, T-lymphocyte function, and the rate of tumor growth. Increasing age is associated with a decreased rate of tumor growth and impaired T-cell function in C57BL/6 mice. Furthermore, when T-cell immunity in young mice is compromised by thymectomy, B16 tumor growth is decreased. Mixed cell transfer studies demonstrated that T cells from young but not old donors stimulate the growth of B16 melanoma cells in young lethally irradiated recipients. Recently, T cells from young but not old mice have been reported to produce angiogenic factors. As tumors from young mice have a richer vascular supply than in old mice, it appears that one mechanism for the age-associated decrease in B16 melanoma growth is the decreased capacity of T cells from old mice to generate angiogenic factors. However, parabiosis of young and old mice showed that local factors in old mice also limit the stimulatory influences of T cells from young mice. Novel therapeutic approaches to limit the growth of tumors might result from a greater understanding of the production of and response to angiogenic factors produced by T cells.

Aging↗
PubMed1989

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 (MoAb's) 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 MoAb's 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.

Aging↗
PubMed1989

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)

Age Factors↗
PubMed1989

Peripheral T cells select the B-cell repertoire in old mice.

These studies have shown that the alterations in the repertoire of antibody produced by old mice is not due to an intrinsic defect in the bone marrow or in the B-lymphocyte population arising from the bone marrow but rather to a selective downregulation by auto-anti-idiotypic antibody and idiotype-anti-idiotype interactions, shifting the idiotype distribution in the peripheral B-cell population. Thus, the clonal distributions of B cells generated by bone marrow of old and young mice are very comparable. The age-related differences in antibodies expressed by young and old mice are, to a great extent, determined by the activity of a peripheral regulatory immune network. This immune cellular network operates prior to exposure to antigen, presumably on the basis of an idiotype-anti-idiotype network between T and B lymphocytes. After exposure to antigen, a network of idiotype-anti-idiotype antibody interactions also contributes to differences in the immune responses of old and young mice to foreign antigens. If the expressed repertoire of antibody reflects down-regulation of auto-anti-idiotypic antibody, comparable repertoires of B-cell clones would be expected to be recovered from old and young mice if B cells from old mice were rescued from selective peripheral downregulatory influences active in old mice. Support for this hypothesis has been obtained by generating B-cell hybridomas from young and old mice immunized with TNP bovine gamme globulin (Marcenario et al. 1989). The same number of anti-TNP hybridomas and a comparable number of IgG and high-affinity antibody-producing clones were recovered from the spleens of young and old mice. Thus, the actual B-cell clonal repertoires of young and old mice appear to be similar although the expressed repertoires of antibody-producing lymphocytes from old and young mice are very different. This conclusion has considerable impact on strategies that could be employed to reverse the senescence of humoral immunity. Strategies to counter downregulatory influences which constrain the expression of the B-cell population should be more effective than attempts to reconstitute the repertoire of B lymphocytes in aged individuals. Finally, the mechanisms underlying these age-associated shifts in the expressed humoral antibody response can be attributed to life-long interactions with self and foreign antigens. The overall shift may be described as a decreased reactivity to foreign antigens and a complementary increase in reactivity with self antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1989

Lymphocyte transformation induced by autologous cells. XVI: Distinctive role of discrete regions of class I MHC antigens in the autologous mixed leucocyte reaction.

The role of Class I major histocompatibility complex (MHC) molecules in the autologous (AMLR) and allogeneic mixed lymphocyte reactions was investigated by using monoclonal antibodies (MoAb) directed to polymorphic MHC determinants. The AMLR from subjects with the HLA-A2 phenotype was consistently inhibited by the anti-HLA-A2 MoAb, CR11-351, and the inhibition was dose-dependent and complete even at low antibody concentrations. The allogeneic MLR was inhibited by CR11-351 less than 30% when HLA-A2-bearing cells were used either as stimulator or responder cells. Addition of interleukins 1 and/or 2 to the AMLR in the presence of the inhibiting MoAbs did not restore the proliferative response. These studies suggest that Class I MHC polymorphic determinants, or closely related structures, participate in the induction of the AMLR.

Antibodies, Monoclonal↗