In this investigation we compare the repopulation of the CD8+ T cell compartments of bone marrow (BM) chimeras by either normal nontransgenic or T cell receptor (TcR) alpha beta-transgenic (TG) CD8+ T cells, the fate of TG and non-TG CD8+ T cells in different parabionts and the survival of TG and non-TG peripheral CD8+ T cells after transfer into athymic hosts. We found that cellular competition among CD8 T cells occurs at several steps of T cell differentiation including a) during the DN to DP transition, b) positive selection in the thymus, c) export from the thymus and d) in the periphery. Comparison of the results obtained in the BM chimeras and in the parabionts shows that an important step of T cell selection occurs during seeding of peripheral lymphoid tissues. Once established, peripheral T cells resist replacement by recent thymus migrants, i.e. in the periphery, selection of T cell repertoires follows the rule "first come, first served". Peripheral dominance correlates with T cell activation and division. Cell cycling and CD44 expression are more frequent among non-TG CD8 T cells than TG CD8 T cells and within the latter, more frequent among P14 TG CD8 T cells than anti-HYTG CD8 T cells. Thus, in the absence of intentional immunization, the frequencies of CD8+ T cells follow a hierarchy of selection in which non-TG > or = P14 TG > anti-HY TG. We also show that the equilibrium size and the fate of one CD8 T cell population differs according to the presence or absence of other CD8 T cell populations. Under these circumstances, selection of T cell repertoires and T cell survival and memory rely not only on the interactions of each T cell with their respective ligands, but also on the nature and number of other competing cells.

The number of peripheral T cells in mice increases up to 100-fold in the first few weeks of life. We have followed the fate of Thy-1 congenic T cells transferred into newborn recipients, to evaluate the relative contribution of thymic output versus peripheral expansion in the constitution of peripheral T cell pools during post-natal development. The results show that in normal animals there is essentially no peripheral expansion of T cells, which show slow turnover rates (1 to 2 months) along that time period. The rates of cell accumulation in the periphery require, therefore, an average of 1 x 10(6)-2 x 10(6) mature thymic emigrants/day for the first 3 weeks of life.

The differential class-regulation of CD4+ T lymphocyte populations is believed to play a major role in determining the qualitative behaviour of the immune system, and in the fate of immune responses in particular. In this article we propose a model for the dynamics of the Th1 and Th2 subpopulations. We put forward the concept of an 'antigenic niche' which allows us to postulate that the key feature underlying the regulation of Th differentiation pathways is the population dynamics of the lymphocytes themselves. Using this model we are able to account for a number of well established experimental observations which were hitherto apparently unrelated and poorly understood. This suggests that our simplified model might be capturing some essential features of the immune system.

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are known to be associated with an increased risk of bleeding. The NSAID, flurbiprofen, in the form of 8.75 mg lozenge or oromucosal spray is indicated for the symptomatic relief of sore throat. Despite the low dose as compared to alternative flurbiprofen preparations, concerns have been raised regarding its safety in terms of haemorrhagic events. This systematic review was conducted to identify existing evidence on the risk of haemorrhagic events with flurbiprofen 8.75 mg dose (any formulation), particularly where this may be due to potential interactions with other medicinal products. The systematic review examined studies reporting haemorrhagic events in patients receiving flurbiprofen 8.75 mg dose. Six individual electronic databases were searched up to 28th April 2020. Records were initially screened for relevance followed by further review of potentially eligible studies. Data extraction was performed for eligible studies and risk of bias in studies was assessed. The search strategy identified 1093 individual records. Of these, 1038 records were excluded after initial review; the majority of these records related to flurbiprofen in alternative formulations with alternative doses (e.g., eye drops, skin patches, oral tablets) thus were not considered relevant for further review. The 55 remaining records related to flurbiprofen 8.75 mg dose (any formulation) or flurbiprofen lozenge/oromucosal spray where the dose was not specified. After further review, 52 of these records were not considered eligible. Thus, only three records were included in this systematic review. The three studies reported a total of five haemorrhagic events in patients taking flurbiprofen 8.75 mg lozenge; the corresponding risk in each of the studies was 8.33, 1.98 and 1.96%. Where possible, comparison of flurbiprofen 8.75 mg lozenge to placebo produced risk ratios of 0.96 (95% CI 0.07, 13.25) and 2.00 (95% CI 0.10, 118.0). This systematic review found limited evidence on the risk of haemorrhagic events with flurbiprofen when used at a dose of 8.75 mg. Counts were low across all studies and results comparing flurbiprofen and placebo treatment arms were non-significant. However, scarcity of studies and low certainty of evidence for the outcome of haemorrhagic events limits the conclusions of this systematic review.