Recall immune memory: a new tool for generating late onset autoimmune myasthenia gravis.
ABSTRACT Most patients with autoimmune myasthenia gravis (MG) produce autoantibodies against their muscle acetylcholine receptors (AChR), causing debilitating muscle weakness. Approximately 60% of MG patients first exhibit myasthenic symptoms after the age of 40. Yet, in the C57BL/6 mouse model of MG, older mice are resistant to induction of myasthenia gravis. To understand the immunological basis for this resistance, the effects of age on the B-cell responses to AChR from Torpedo californica, the inducing antigen, were addressed. As expected, the primary B-cell response was lower in 20-month-old mice than in 2-month-old mice; the isotype profile was not altered by age. When mice were re-immunized, the anti-T-AChR titers increased in both young and old animals, suggesting that a memory response was elicited. Importantly, memory B-cells activated in young animals were largely resistant to the age-associated loss of immune function and the recall memory response was vigorous. Furthermore, the antibodies produced in re-stimulated older mice were functional, as evidenced by the appearance of MG symptoms in some of these animals. Thus, by eliciting a recall memory response, the first examples of late onset MG in mice have been generated. By analogy, late onset MG in humans may be due to re-activation of B-cell responses initiated at a younger age.
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ABSTRACT: Cancer is a disease of the elderly. Since demographic trends indicate that over the next decades the number of elderly people will increase substantially, strategies for cancer prevention and therapy need to be optimized to older patients. Immunotherapy, either through passive or active immunization is a highly targeted type of therapy that is potentially less toxic than chemotherapy or radiation and could, therefore, be especially effective in older, more frail cancer patients. In particular active immunization, i.e., employing patient’s own immune system through vaccination, offers great promise since it can potentially keep cancer permanently at bay. However, it has been shown that older individuals do not respond to vaccine therapy as well as younger adults. This has been attributed to diminished T-cell responses, a phenomenon also observed in cancer patients per se. To develop cancer vaccines that are effective at older age, the availability of preclinical models that can predict age effects on cancer vaccination is critically important. In this review, current knowledge of diminished T-cell responses in cancer patients and elderly, the results of cancer vaccination in preclinical models and human clinical trials and the impact of aging on immunotherapy will be discussed. Finally, experimental approaches will be proposed how to make cancer vaccines more effective at older age.
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ABSTRACT: Cancer vaccination is less effective at old than at young age, due to T cell unresponsiveness, caused by various age-related changes of the immune system. This includes lack of naïve T cells, defects in activation pathways of T cells and antigen-presenting cells (APC), and age-related changes in the tumor microenvironment. Although evidence exists that also natural killer (NK) and natural killer T (NKT) cells of the innate immune system change with age, comparison of various studies involving adaptive and innate immune responses in elderly and cancer patients, as well as cancer vaccination at young and old age in this review, indicates that also innate immune responses should be tested as a potential candidate to improve immunotherapy against cancer at older age.Current opinion in immunology 07/2011; 23(4):555-60. DOI:10.1016/j.coi.2011.05.003 · 7.87 Impact Factor
Article: Aging and cancer vaccines.[Show abstract] [Hide abstract]
ABSTRACT: Cancer vaccination is less effective at old than at young age, due to T cell unresponsiveness. This is caused by age-related changes of the immune system. Major immune defects at older age are lack of naive T cells, impaired activation pathways of T cells and antigen-presenting cells (APC), and age-related changes in the tumor microenvironment (TME). Also innate immune responses are affected by aging, but this seems less abundant than adaptive immune responses. In this review we compared various cancer vaccine studies at young and old age, demonstrating the importance of both innate and adaptive immune responses for cancer immunotherapy. Moreover, we found suggestive evidence that innate immune responses could help improve adaptive immune responses through cancer vaccination in old age.Critical reviews in oncogenesis 01/2013; 18(6):585-95. DOI:10.1615/CritRevOncog.2013010588