26 research outputs found
The effect of interrupted anti-retroviral treatment on the reconstitution of memory and naive T cells during tuberculosis treatment in HIV patients with active pulmonary tuberculosis
Background: The reconstitution of cellular immune components contributes to clinical outcome of HIV and Mycobacterium tuberculosis (MTB) infection. Interruption of anti-retroviral therapy (ART) could lead to perturbations in reconstitution of T cells in HIV/ tuberculosis (TB) patients. Objectives: To ascertain the effect of interrupted ART on reconstitution of CD4+ and CD8+ T sub-sets in TB patients.Methods: Participants with HIV (CD4>350 cells/μL) and TB were recruited under a larger phase 3 open label randomised controlled clinical trial. The CD45RO and CD62L markers were measured on CD4+ and CD8+ cells by flow cytometry. Samples were analysed at baseline, 3, 6, 12 months.Results: There was a significant increase of naive CD8+ cells (p = 0.003) and a decrease in effector CD8+ cells (p = 0.004) among participants in ART/TB treatment arm during the first 6 months. Withdrawing ART led to naive CD8+ cells reduction (p=0.02) to values close to baseline. An increase of naive CD8+ cells after 6 months of TB treatment in TB alone treatment arm (p=0.01) was observed. A trend towards increment of naive CD4+ sub sets in either treatment arms was observed.Conclusion: Interrupting ART alters CD8+ but not CD4+ sub-sets in patients with less advanced HIV infection and TB.Keywords: Interrupted anti-retroviral treatment, memory and naive T cells, HIV patients, active pulmonary tuberculosis
The effect of interrupted anti-retroviral treatment on the reconstitution of memory and naive T cells during tuberculosis treatment in HIV patients with active pulmonary tuberculosis.
Background: The reconstitution of cellular immune components
contributes to clinical outcome of HIV and Mycobacterium tuberculosis
(MTB) infection. Interruption of anti-retroviral therapy (ART) could
lead to perturbations in reconstitution of T cells in HIV/ tuberculosis
(TB) patients. Objectives: To ascertain the effect of interrupted ART
on reconstitution of CD4+ and CD8+ T sub-sets in TB patients. Methods:
Participants with HIV (CD4>350 cells/\ub5L) and TB were recruited
under a larger phase 3 open label randomised controlled clinical trial.
The CD45RO and CD62L markers were measured on CD4+ and CD8+ cells by
flow cytometry. Samples were analysed at baseline, 3, 6, 12 months.
Results: There was a significant increase of naive CD8+ cells (p =
0.003) and a decrease in effector CD8+ cells (p = 0.004) among
participants in ART/TB treatment arm during the first 6 months.
Withdrawing ART led to naive CD8+ cells reduction (p=0.02) to values
close to baseline. An increase of naive CD8+ cells after 6 months of TB
treatment in TB alone treatment arm (p=0.01) was observed. A trend
towards increment of naive CD4+ sub sets in either treatment arms was
observed. Conclusion: Interrupting ART alters CD8+ but not CD4+
sub-sets in patients with less advanced HIV infection and TB
Neurodevelopment and recovery from wasting
BACKGROUND AND OBJECTIVES
Acute illness with malnutrition is a common indication for hospitalization among children in low- and middle-income countries. We investigated the association between wasting recovery trajectories and neurodevelopmental outcomes in young children 6 months after hospitalization for an acute illness.
METHODS
Children aged 2 to 23 months were enrolled in a prospective observational cohort of the Childhood Acute Illness & Nutrition Network, in Uganda, Malawi, and Pakistan between January 2017 and January 2019. We grouped children on the basis of their wasting recovery trajectories using change in mid–upper arm circumference for age z-score. Neurodevelopment was assessed with the Malawi Developmental Assessment Tool (MDAT development-for-age z-score [DAZ]) at hospital discharge and after 6 months.
RESULTS
We included 645 children at hospital discharge (mean age 12.3 months ± 5.5; 55% male); 262 (41%) with severe wasting, 134 (21%) with moderate wasting, and 249 (39%) without wasting. Four recovery trajectories were identified: high–stable, n = 112; wasted–improved, n = 404; severely wasted–greatly improved, n = 48; and severely wasted–not improved, n = 28. The children in the severely wasted–greatly improved group demonstrated a steep positive MDAT-DAZ recovery slope. This effect was most evident in children with both wasting and stunting (interaction wasted–improved × time × stunting: P < .001). After 6 months, the MDAT DAZ in children with wasting recovery did not differ from community children. In children who never recovered from wasting, there remained a significant delay in MDAT DAZ scores.
CONCLUSIONS
Neurodevelopment recovery occurred in parallel with wasting recovery in children convalescing from acute illness and was influenced by stunting
Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4+ T Cell Activation via Toll-Like Receptors 1 and 2â–¿
The success of Mycobacterium tuberculosis as a pathogen relies on its ability to regulate the host immune response. M. tuberculosis can manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role of M. tuberculosis molecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules in M. tuberculosis lysate responsible for costimulation of primary human CD4+ T cells. In the absence of APCs, activation of memory CD4+ T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4+ T cells can use TLR2/TLR1 heterodimers to directly respond to M. tuberculosis products. M. tuberculosis lipoproteins induced NF-κB activation in CD4+ T cells in the absence of TCR co-engagement. Thus, TLR2/TLR1 engagement alone by M. tuberculosis lipoprotein triggered intracellular signaling, but upregulation of cytokine production and proliferation required co-engagement of the TCR. In conclusion, our results demonstrate that M. tuberculosis lipoproteins LprG and LpqH participate in the regulation of adaptive immunity not only by inducing cytokine secretion and costimulatory molecules in innate immune cells but also through directly regulating the activation of memory T lymphocytes
Longitudinal TST measurements among HHC.
<p>TST were placed at study enrollment and every 3-month course of INH preventive therapy and post-conversion TST was placed 12 months following each subject's initial conversion event. Following measurement of post-conversion TST, subjects were classified as either stable converters or reverters. Shown are mean TST measurements (mm) ± 1 SD for all eligible study participants at study enrollment (baseline), conversion, and post-conversion time points (A). As shown in Panel B (numbers in boxes indicate number of conversions per time point), subjects with stable conversions were more likely to experience their initial conversion soon following study entry (mean time to conversion, 4.1 months) while reverters experienced their initial conversion later (mean time to conversion 7.2 months; p = 0.03).</p
Tuberculin Skin Test Reversion following Isoniazid Preventive Therapy Reflects Diversity of Immune Response to Primary <i>Mycobacterium tuberculosis</i> Infection
<div><p>Rationale</p><p>Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent <i>Mycobacterium tuberculosis</i> (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.</p><p>Objectives</p><p>To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion.</p><p>Methods</p><p>Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion <i>vs.</i> reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT.</p><p>Results</p><p>Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters.</p><p>Conclusions</p><p>TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.</p></div