Role of dendritic cells in induction of tolerance and immunity in vivo.
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Adoptive Transfer↗
Biomedical subjects
M C Cook
Publications and source records attributed to M C Cook.
The role of T cells in the regulation of B cell tolerance.
The study of conventional models of B cell tolerance has suggested that self-tolerance is imposed on B cells at an early stage in their development due to a peculiar sensitivity of immature B cells to tolerance induction. While this concept accounts for some aspects of central B cell tolerance, it is inconsistent with recent reports of tolerance induction in mature splenic B cells from immunoglobulin transgenic mice. We present an alternative model, the hierarchical model (Aust. N. Z. J. Med. 25, 761-767, 1995), in which regulation of naive B cell reactivity is a function of antigen signal strength and availability of T cell help, but is independent of B cell maturation stage. In turn, the development of tolerance or memory in the T cell compartment is dependent on a combination of antigen-MHC recognition by T cells and antigen-nonspecific signalling by antigen-presenting cells. Using a transgenic model of T-B collaboration, we have shown that both immature and mature self-reactive B cells can be rescued and induced to secrete auto-antibody if the B cell determinant is linked to a carrier protein bearing a foreign T cell determinant.
Animals↗
The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.
Self-reactive B cells from tolerant double-transgenic (Dbl-Tg) mice coexpressing hen egg lysozyme (HEL) and rearranged anti-HEL immunoglobulin genes have a relatively short life span when compared to normal B cells, irrespective of whether they are exposed to antigen in multivalent membrane-bound form (mHEL-Dbl-Tg mice) or soluble form (sHEL-Dbl-Tg mice). The factors responsible for determining the fate of these B cells after encounter with self-antigen were investigated using a cell-tracking technique in which anti-HEL Ig-Tg spleen cells were labeled with the intracellular dye 5-carboxyfluorescein diacetate-succinimidyl ester (CFSE) and injected either into non-Tg recipients or a variety of HEL-Tg hosts. In non-Tg recipients, HEL-binding B cells persisted in the circulation and could be detected in the follicles of the spleen for at least 5 d. On transfer into either mHEL-Tg or sHEL-Tg hosts, they underwent activation and then rapidly disappeared from the blood and spleen over the next 3 d, consistent with the short life span reported previously. Immunohistology of spleens from sHEL-Tg recipients indicated that the transferred B cells had migrated to the outer margins of the periarteriolar lymphoid sheath (PALS), where they were detectable for 24 h before being lost. The positioning of B cells in the outer PALS depended on a critical threshold of Ig receptor binding corresponding to a serum HEL concentration between 0.5 and 15 ng/ml, but was not restricted to endogenously expressed HEL in that the same migratory pattern was observed after transfer into non-Tg recipients given exogenous (foreign) HEL. Moreover, bone marrow-derived immature Ig-Tg B cells homed to the outer PALS of sHEL-Tg mice and then disappeared at the same rate as mature B cells, indicating that the stage of maturation did not influence the fate of self-reactive B cells in a tolerant environment. On the other hand, HEL-binding B cells transferred into sHEL-Dbl-Tg recipients persisted over the 3-d period of study, apparently due to insufficient availability of antigen, as indicated by the fact that the degree of Ig receptor downregulation on the transferred B cells was much less than in sHEL-Tg recipients. If T cell help was provided to Ig-Tg B cells at the time of transfer into sHEL-Tg recipients in the form of preactivated CD4+ T cells specific for major histocompatibility complex-peptide complexes on the B cell surface, HEL-binding B cells migrated through the outer PALS of the spleen to the follicle, where they formed germinal centers, or to adjacent red pulp, where they formed proliferative foci and secreted significant amounts of anti-HEL antibody. Taken together, these results indicated that the outcome of the interaction between self-antigen and B cells is largely determined by a combination of the degree of receptor engagement and availability of T cell help.
Amino Acid Sequence↗
Nutritional implications of medication use and misuse in elderly.
Factors responsible for an increased risk of drug-nutrient interactions in the elderly are an increased exposure to drug use for chronic health conditions and the greater chance for marginal diets deficient in nutrients. Poor patient compliance and physicians' prescribing patterns further complicate the risk. Several nutrient-drug interactions cause changes in drug efficacy and affect nutritional status. To identify and assess elderly patients at risk, each should be evaluated through socioeconomic, dietary, and clinical parameters. The health-care team must be knowledgeable regarding drug interactions to properly intervene using a multidisciplinary approach. An intervention program could prevent a decline in the elderly's health status, reduce healthcare costs and improve the quality of life.
Aged↗
Noninvasive estimation of extravascular lung water using bioimpedance.
Currently, accurate measurements of extravascular lung water (EVLW) are obtained using the double dye dilution technique (DD). However, this method is invasive and complicated and has limited its clinical use. The purpose of this study was to develop a noninvasive method for determining changes in EVLW using bioimpedance (BI) and compare these measurements with DD in a model of acute pulmonary injury. Nine adult dogs were anesthetized and instrumented with a pulmonary artery and an EVLW arterial catheter with EVLW-DD and cardiac output calculated from the dye and thermal dilution curves. Eight external electrodes were placed on the thorax and impedance changes were measured by computer. Changes in EVLW-BI were computed as a function of the thoracic volume and impedance. Cardiac output (CO) from BI was obtained by electronically differentiating the bioimpedance signal. EVLW and CO were measured using DD and BI at 0, 15, 30, and 60 min following injection of oleic acid (0.1 cc/kg). Changes in EVLW were correlated over all time periods using DD and BI (r = 0.70, P less than 0.05); however, several impedance EVLW estimates varied greatly from double dilution methods. There was no difference in computed EVLW using DD and BI at 15, 30, and 60 min following oleic acid infusion (P greater than 0.35). CO was significantly correlated using DD and BI (r = 0.81, P less than 0.05). In summary, bioimpedance may hold promise as a noninvasive and continuous means for estimation of EVLW in the critical care setting.
Animals↗