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Alloreactive CD154-expressing T-cell subsets with differential sensitivity to the immunosuppressant, belatacept: potential targets of novel belatacept-based regimens.

ABSTRACT: Belatacept blocks CD28-mediated T-cell costimulation and prevents renal transplant rejection. Understanding T-cell subset sensitivity to belatacept may identify cellular markers for immunosuppression failure to better guide treatment selection. Here, we evaluate the belatacept sensitivity of allo-antigen-specific CD154-expressing-T-cells, whose T-cytotoxic memory (TcM) subset predicts rejection with high sensitivity after non-renal transplantation. The belatacept concentration associated with half-maximal reduction (EC50) of CD154 expression was calculated for 36 T-cell subsets defined by combinations of T-helper (Th), Tc, T-memory and CD28 receptors, following allostimulation of peripheral blood leukocytes from 20 normal healthy subjects. Subsets were ranked by median EC50, and by whether subset EC50 was correlated with and therefore could be represented by the frequency of other subsets. No single subset frequency emerged as the significant correlate of EC50 for a given subset. Most (n = 25) T-cell subsets were sensitive to belatacept. Less sensitive subsets demonstrated a memory phenotype and absence of CD28 receptor. Potential drug-resistance markers for future validation include the low frequency highly differentiated, Th-memory-CD28-negative T-cells with the highest median EC50, and the least differentiated, high-frequency Tc subset, with the most CD28-negative T-cells, the third highest median EC50, and significant correlations with frequencies of the highest number of CD28-negative and memory subsets.

SUBMITTER: Ashokkumar C

PROVIDER: S-EPMC4607954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nerve growth factor is an inflammatory mediator that induces long-lasting hyperalgesia, which can partially be attributed to nerve growth factor-induced sensitization of primary afferent nociceptors. It was shown that nerve growth factor increases the excitability of polymodal C-fibre nociceptors by modulating tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium channels, but hitherto only little is known about the effects of nerve growth factor on sodium currents in other nociceptor subtypes that express the nerve growth factor receptor TrkA. We previously characterized two reporter mouse lines that allow the unequivocal identification of two important subclasses of TrkA-expressing nociceptors - i.e. neuropeptide Y receptor type 2 (NPY2R+ ) A?-fibre nociceptors that mediate pinprick pain and nicotinic acetylcholine receptor alpha-3 subunit (CHRNA3+ ) silent nociceptors, which are the most abundant TrkA+ nociceptors in visceral organs and deep somatic tissues. Here, we utilized these mouse lines to investigate the expression patterns and the possible nerve growth factor-dependent modulation of sodium channels in these neurons using whole-cell patch-clamp recordings and quantitative real-time polymerase chain reaction. We demonstrate that NPY2R+ nociceptors, CHRNA3+ 'silent' nociceptors and polymodal C-fibre nociceptors express different combinations of sodium channel ?- and ?-subunits and accordingly exhibit functionally different sodium currents. Moreover, we demonstrate that nerve growth factor produces robust hyperpolarizing shifts in the half-activation voltage of tetrodotoxin-resistant currents in NPY2R+ nociceptors and polymodal C-fibre nociceptors and also shifts the half-activation of tetrodotoxin-sensitive currents in polymodal C-fibre nociceptors. In silent nociceptors, however, nerve growth factor solely increases the current density of the tetrodotoxin-resistant current but does not alter other sodium channel properties. Considering the different peripheral target tissues and the previously reported roles in different forms of pain of the nociceptor subpopulations that were examined here, our results suggest that nerve growth factor differentially contributes to the development visceral and cutaneous pain hypersensitivity and highlights the importance of developing different therapeutic strategies for different forms of pain.

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Alloreactive CD154-expressing T-cell subsets with differential sensitivity to the immunosuppressant, belatacept: potential targets of novel belatacept-based regimens.

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