Modulation of human lymphocyte proliferative response with aging.
Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.
Douziech
Nadine
N
Centre de Recherche en Gérontologie et Gériatrie, Institut Universitaire de Gériatrie de Sherbrooke, 1036 rue Belvedère sud, Sherbrooke, Quebec, Canada J1H 4C4.
Seres
Ildikò
I
Larbi
Anis
A
Szikszay
Edit
E
Roy
Pierre Michel
PM
Arcand
Marcel
M
Dupuis
Gilles
G
Fulop
Tamàs
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014810:Vitamin E / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D000975:Antioxidants; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D010835:Phytohemagglutinins; D011994:Recombinant Proteins; D014810:Vitamin E; D002784:Cholesterol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid