Interestingness: 3
By JD Robertson and RF Wynn, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 389-395, doi:10.1089/rej.1.2000.3.389)
Review of what was known about telomere length and telomerase in blood cells. Haemopoietic stem cells (HSC) have active telomerase but their telomeres shorten gradually. Same for T-cells. Telomeres in neutrophils also shorten at about the same rate as in T-cells (20-50 base pairs per year), but from what I understood, they don't have active telomerase, so the telomerase is acting as a compensation method for the occasional clonal expansion of T-cells.
Checking for which X chromosome is inactivated, in old women most blood cells have the same one, as if they come from fewer and fewer stem cells.
In people with acute leukemia, telomeres are short and telomerase long, and they suggest this suggests that telomerase activates late in the process of disease. Also short telomeres on aplastic anemia and Fanconi's anemia. Also shorter telomeres in bone marrow transplant recipients than in donors (about 15 years worth), but I'm not clear if they are saying this is because the transplanted tissue has had to undergo quick replication to refill the recipient's system, or that this was there before.
Showing posts with label t-cell. Show all posts
Showing posts with label t-cell. Show all posts
Tuesday, January 3, 2012
Monday, January 2, 2012
DNA Damage and Telomere Length in Human T Cells
Interestingness: 3
By Yvonne A Barnett, Christopher R Barnett, and Thomas Von Zglinicki, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 383-388, doi:10.1089/rej.1.2000.3.383. )
Seemed speculative on the link between T-cell, telomere length and oxidation damage in vivo, but presented a series of facts to suggest a link: increasing mutations in one particular gene in lymphocytes with age, senescent-looking T-cells in vivo in centenarians and people with Down's syndrome, and fibroblast with higher anti-oxidant capacity having a slower telomere shortening rate in vitro.
(Interesting: link between shorter telomeres and vascular dementia, but not with Alzheimer's, stroke or heart attack)
By Yvonne A Barnett, Christopher R Barnett, and Thomas Von Zglinicki, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 383-388, doi:10.1089/rej.1.2000.3.383. )
Seemed speculative on the link between T-cell, telomere length and oxidation damage in vivo, but presented a series of facts to suggest a link: increasing mutations in one particular gene in lymphocytes with age, senescent-looking T-cells in vivo in centenarians and people with Down's syndrome, and fibroblast with higher anti-oxidant capacity having a slower telomere shortening rate in vitro.
(Interesting: link between shorter telomeres and vascular dementia, but not with Alzheimer's, stroke or heart attack)
Sunday, October 24, 2010
Importance of T-Cell Replicative Senescence for the Adoptive Immunotherapy of Cancer in Humans?
Summary: Review of replication of T-cells in vitro
Interestingness: 3
Paper by Graham Pawelec in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.
(((
This is another paper on T-cell senescence (previous one here: http://readingrejuvenationresearch.blogspot.com/2010/06/immunosenescence-analysis-and-genetic.html). It focuses on in-vitro studies, saying they are clinically important since that is how immune therapies will likely work best (eg training T-cells on tumor cells outside the body and then reinserting them) to work around the low immune responses of old people. I think their main area of investigation is trying to optimise the conditions under which T-cells replicate the longest.
It says the average number of population doublings (PD) of a T-cell in vitro before it becomes senescent, when externally stimulated, is 17, but 33 for cells that manage to get "established" (ie they get to a million cells). Seems like a very arbitrary cutoff but it better matches the numbers in the previous paper (25-40). The longest living ones reach 80 PDs on average and their record is around 170. They don't know why the large variability exists. The age of the person they were taking from doesn't seem to be one of the important variables. Longevity of CD34+ stem cells differentiated in vitro is no different to that of mature CD3+ cells.
They then switch to the link between telomeres and senescence. Fibroblast telomere length is directly proportional to replicative capacity. They say that this might apply to lymphocytes since the telomere lengths of human blood cells ex vivo are related to donor age, and the rate of telomere shortening with each doubling is about the same as for fibroblasts (120 bp per cell doubling). To me this would contradict what they said before that the replicative longevity was not related to the age of the donor, unless they mean blood cells other than T-cells.
In experiments by other people (Weng, Levine, June, et al) they found that CD4+ memory cells have shorter telomeres than naive cells, and that the difference is independent of the age of the donor. Telomere length decreases during autocrine replication of both of these and naive cells have higher replicative longevity than memory cells. The authors of this paper say this might not give the same results if externally stimulated replication was being used, since this can go on for way longer than the capacity for the cells to secrete interleukin-2, which triggers replication under autocrine replication, and that it doesn't necessarily follow that telomere length is the determining cause of senescence. Telomerase activity is upregulated in T cells when stimulated with CD3 and CD28 simultaneously but this might not happen optimally under various experimental setups, and might not happen optimally in-vivo due to decreased expression of CD28 with age. This, they say, might be the driving mechanism to senescence.
From small experiments they ran on oldish (<35 PD) and older (>43 PD) CD4+ cells, they noticed an upregulation of three mitotic inhibitors (p16-INK4alpha, p21-WAF, and p27-kip1) which suggest that upregulation of mitotic inhibitors might be an alternative hypothesis as the cause of senescence.
)))
Abstract follows:
Interestingness: 3
Paper by Graham Pawelec in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.
(((
This is another paper on T-cell senescence (previous one here: http://readingrejuvenationresearch.blogspot.com/2010/06/immunosenescence-analysis-and-genetic.html). It focuses on in-vitro studies, saying they are clinically important since that is how immune therapies will likely work best (eg training T-cells on tumor cells outside the body and then reinserting them) to work around the low immune responses of old people. I think their main area of investigation is trying to optimise the conditions under which T-cells replicate the longest.
It says the average number of population doublings (PD) of a T-cell in vitro before it becomes senescent, when externally stimulated, is 17, but 33 for cells that manage to get "established" (ie they get to a million cells). Seems like a very arbitrary cutoff but it better matches the numbers in the previous paper (25-40). The longest living ones reach 80 PDs on average and their record is around 170. They don't know why the large variability exists. The age of the person they were taking from doesn't seem to be one of the important variables. Longevity of CD34+ stem cells differentiated in vitro is no different to that of mature CD3+ cells.
They then switch to the link between telomeres and senescence. Fibroblast telomere length is directly proportional to replicative capacity. They say that this might apply to lymphocytes since the telomere lengths of human blood cells ex vivo are related to donor age, and the rate of telomere shortening with each doubling is about the same as for fibroblasts (120 bp per cell doubling). To me this would contradict what they said before that the replicative longevity was not related to the age of the donor, unless they mean blood cells other than T-cells.
In experiments by other people (Weng, Levine, June, et al) they found that CD4+ memory cells have shorter telomeres than naive cells, and that the difference is independent of the age of the donor. Telomere length decreases during autocrine replication of both of these and naive cells have higher replicative longevity than memory cells. The authors of this paper say this might not give the same results if externally stimulated replication was being used, since this can go on for way longer than the capacity for the cells to secrete interleukin-2, which triggers replication under autocrine replication, and that it doesn't necessarily follow that telomere length is the determining cause of senescence. Telomerase activity is upregulated in T cells when stimulated with CD3 and CD28 simultaneously but this might not happen optimally under various experimental setups, and might not happen optimally in-vivo due to decreased expression of CD28 with age. This, they say, might be the driving mechanism to senescence.
From small experiments they ran on oldish (<35 PD) and older (>43 PD) CD4+ cells, they noticed an upregulation of three mitotic inhibitors (p16-INK4alpha, p21-WAF, and p27-kip1) which suggest that upregulation of mitotic inhibitors might be an alternative hypothesis as the cause of senescence.
)))
Abstract follows:
Replicative senescence may compromise T cell-dependent immune responses to intermittent or chronic antigenic stimulation. While the impact of senescence in vivo remains hard to ascertain, clonal cultures of T cells in vitro provide models for longitudinal studies of aging in well-defined populations. Functional and phenotypic studies as well as investigations into average and maximal longevity of T cells can be performed conveniently with these cloned cells (the former in fact only with cloned cells). Many of the age-associated alterations observed during culture in vitro have also been noted ex vivo in T cells from the elderly.
Moreover, under circumstances where large numbers of antigen- and function-specific T cells may be required, for example for adoptive immunotherapy, the in vitro longevity of the cells may be critically important to successful outcome. These considerations are discussed in the following commentary in the context of immunotherapy of cancer.
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