Biomedical subjects

M D Hazenberg

Publications and source records attributed to M D Hazenberg.

4 recordsLinked to original sources

PubMed2001

T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation.

T cell differentiation in the thymus is characterized by a hierarchical order of rearrangement steps in the T cell receptor (TCR) genes, resulting in the joining of V, D, and J gene segments. During each of the rearrangement steps, DNA fragments between rearranging V, D, and J gene segments are deleted as circular excision products, the so-called TRECs (T cell receptor excision circles). TRECs are assumed to have a high over-time stability, but they can not multiply and consequently are diluted during T cell proliferation. It was recently suggested that quantitative detection of TRECs would allow for direct measurement of thymic output. The deltaRec-psiJalpha TREC appears to be the best marker, because the majority of thymocyte expansion occurs before this TREC is formed. However, apart from thymic output several other factors determine the TREC content of a T cell population, such as cell division and cell death. Likewise, the number of TRECs depends not only on thymic output, but also on the longevity of naive T cells. This warrants caution with regard to the interpretation of TREC data as measured in healthy and diseased individuals. deltaRec-psiJalpha TREC detection is a new and elegant tool for identification of recent thymic emigrants in the periphery, but further research is required for making quantitative estimations of thymic output with the use of TREC analysis.

Animals↗

PubMed2000

T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART).

In human immunodeficiency virus (HIV)-1 infection, highly increased T-cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4(+) and CD8(+) lymphocyte subpopulations before and during highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67(+) CD4(+) and CD8(+) lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4(+) T cells in the blood was found when the number of these cells were below 100 per microL. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4(+) T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4(+) CD27(+) memory pool. In the CD8(+) T-cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27(+) CD 45RO(+) and CD27(-) CD45RO(+) memory CD8(+) T-cell pool, corresponding with the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8(+) T-cell subsets. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)

Anti-HIV Agents↗

PubMed2000

Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection.

Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation.

Anti-HIV Agents↗

PubMed2000

T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock.

HIV-1 infection is characterized by a gradual loss of CD4+ T cells and progressive immune deficiency that leads to opportunistic infections, otherwise rare malignancies and ultimately death. Extensive research over the past two decades has increased our insight into the pathogenic mechanisms underlying these features of HIV-1 infection. Here, we will give a brief overview of the most recent findings and present a model that fits most of the relevant aspects of HIV-1 infection as known. We hypothesize that HIV-1 infection depletes T cell supplies (which are not replaced because of low and static thymic function) by direct infection and killing of cells and through hyperactivation of the immune system.

CD4-Positive T-Lymphocytes↗