Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

Estimation of the time-dependent vaccine efficacy from a measles epidemic.

We present a method to estimate the time-dependent vaccine efficacy from the cohort-specific vaccination coverage and from data on the vaccination status of cases and apply it to a measles epidemic in Germany which involved 529 cases, 88 of whom were vaccinated and 370 unvaccinated (for the remaining 71 cases the vaccination status is unknown). Our epidemiological model takes into account that maternal antibodies prevent successful vaccination and that vaccine immunity may be lost over time. Model parameters are estimated from the data using maximum likelihood. Vaccination coverage, as determined in school surveys, ranged from 27.6 per cent for the cohort born in 1974 to 85 per cent for the 1986 cohort, which is far too low to prevent measles transmission. Cohorts for which no school surveys were performed are omitted from analysis. Thus, sufficient data are available for only 282 cases, 69 of whom are vaccinated. According to our estimates, measles vaccinations provided no immunity before 1978 (95 per cent CI: 0 to 47 percent), for the period 1978-1982, the estimated vaccine efficacy was 80 percent (95 percent CI: 67 to 89 percent), and for 1982-1990 it was 97 percent (95 percent CI: 93 to 99 percent). After 1990, the estimated value dropped to 89 per cent, but its confidence interval widely overlaps with that of the previous period (95 percent CI: 74 to 97 percent). Loss of immunity was estimated to be zero (95 percent CI: 0 to 0.003/year). Several sensitivity analyses were performed with respect to the model assumptions. A modified model which assumed constant efficacy at all vaccination times yielded a high estimate of 96 per cent (95 percent CI: 92 to 98 percent) for primary vaccine efficacy but also a high loss rate of immunity of 0.007/year (95 percent CI: 0.001 to 0.012) to explain the high fraction of vaccinated cases among older individuals. The likelihood score value is however significantly inferior compared to the score value of the model with time-dependent vaccine efficacy.

Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data.

Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

Plasmodium falciparum parasitaemia described by a new mathematical model.

A new mathematical model of Plasmodium falciparum asexual parasitaemia is formulated and fitted to 35 malaria therapy cases making a spontaneous recovery after primary inoculation. Observed and simulated case-histories are compared with respect to 9 descriptive statistics. The simulated courses of parasitaemia are more realistic than any previously published. The model uses a discrete time-step of 2 days. Its realistic behaviour was achieved by the following combination of features (i) intra-clonal antigenic variation, (ii) large variations of the variants' baseline growth rate, depending on both variant and case, (iii) innate autoregulation of the asexual parasite density, variable among cases, (iv) acquired variant-specific immunity and (v) acquired variant-transcending immunity, variable among cases. Aspects of the model's internal behaviour, concerning variant dynamics, as well as the respective contributions of the three control mechanisms (iii) - (v), are displayed. Some implications for pathogenesis and control are discussed.

Modelling the transition of asexual blood stages of Plasmodium falciparum to gametocytes.

In this paper, we investigate the transition of asexual blood stages of P. falciparum to gametocytes. The study is based on daily data, collected from 262 individual courses of parasitaemia. We propose several mathematical models that follow biological reasoning. The models are fitted with maximum likelihood and are compared with each other. The models differ in the assumptions made about the mortality of circulating gametocytes and about the transition rate of the asexual parasites. Gametocyte mortality is modelled as being (i) constant over time, (ii) linearly increasing over time, (iii) linearly increasing over gametocyte age, and (iv) exponentially increasing over gametocyte age, respectively. The transition rate is either kept constant per patient or piecewise constant within intervals that correspond to waves of asexual parasitaemia which are assumed to be caused by different Pf(emp1)-variants. According to likelihood ratio tests, the models with age-dependent mortality rate and wave-dependent transition rates are superior to the models with constant transition rate and/or constant or time-dependent mortality rate. The best fits are reached for models with exponentially increasing (Gompertz-type) mortality. Furthermore, an impact of high asexual parasite densities on the survival of gametocytes, interpreted as a cytokine-mediated effect, is evident in some cases.