Anti-CD13 Abs in children with extensive chronic GVHD and their relation to soluble CD13 after allogeneic blood and marrow transplantation from a Children's Oncology Groups Study, ASCT0031.

Our group previously demonstrated a strong association between elevated plasma soluble CD13 enzyme activity and newly diagnosed extensive chronic GVHD (cGVHD) in children. As cytotoxic anti-CD13 Abs have been documented after blood and marrow transplant (BMT) in association with CMV infection and cGVHD, we hypothesized that soluble CD13 contributes to cGVHD pathogenesis by induction of CD13 reactive Abs and that anti-CD13 Abs could be additional biomarkers for newly diagnosed pediatric extensive cGVHD. Using prospectively collected plasma samples from pediatric allogeneic BMT (allo-BMT) subjects with cGVHD and controls without cGVHD enrolled in a large multi-institution Children's Oncology Group cGVHD therapeutic trial, we evaluated whether soluble CD13 correlates with induction of anti-CD13 Abs. We found that CD13 reactive Abs are present in a proportion of patients after allo-BMT, but did not seem to correlate with the presence of soluble CD13. Anti-CD13 Abs also did not meet our criteria as a diagnostic biomarker for cGVHD. These data do not confirm that induction of CD13 reactive Abs is a mechanism for cGVHD in children nor are part of the pathogenesis of cGVHD associated with elevated soluble CD13. The exact role of CD13 in cGVHD remains to be determined.

The involvement of TLR2 in cytokine and reactive oxygen species (ROS) production by PBMCs in response to Leishmania major phosphoglycans (PGs).

In the present study, we show for the first time that lipophosphoglycan (LPG) stimulated cytokine production by human peripheral blood mononuclear cells is also mediated via Toll-like receptor (TLR2). In addition, in order to verify if TLR2 is involved in recognition of the purified PGs, neutralizing mAbs against TLR2 and TLR4 were used to treat the cells before being stimulated with PGs. We found strong Th1-promoting cytokines induced by sLPG but not by mLPG which was blocked by presence of anti-TLR2 mAb. This finding reveals a mechanism by which the first encounter and recognition of L. major promastigotes by mLPG after interaction with TLR2 provides a cytokine milieu for consequent Th2 differentiation. Moreover, having shown the strong induction of Th1-promoting cytokines and low production of IL-10 in response to sLPG might have vaccine implication since it is recognized by TLR2 providing signals to professional antigen presenting cells that reside in the skin to promote effective T cell responses against Leishmania infection. In addition, it was shown that purified mLPG and sLPG activate reactive oxygen species (ROS) production which is also blocked by anti-TLR2 but not by anti-TLR4. However, no inhibition was seen in PPG-induced cytokine and ROS production in the presence of anti-TLR2 and anti-TLR4, implying involvement of other receptors.

Extreme cause-specific mortality in a cohort of adult prisoners--1988 to 2002: a data-linkage study.

OBJECTIVES: Describe the standardized mortality ratio (SMR) and its trend in adults who have served time in prison. DESIGN: A retrospective cohort study of 85,203 adults imprisoned in New South Wales (NSW), Australia, between 1 January 1988 and 31 December 2002. METHODS: We obtained information on deaths by record linkage with the Australian National Death Index (NDI). Mortality rates were estimated using the person-time method. SMRs were calculated using sex, age, and calendar-specific death rates from the NSW population. Time trends in SMRs were assessed using the test for linear trends. RESULTS: The median overall follow-up of the cohort was 7.7 years. We identified 5137 deaths (4714 men, 423 women) among the cohort of which the vast majority (4834, 94%) occurred following release from custody. All-cause SMR was 3.7 (95% CI: 3.6-3.8) in men and 7.8 (95% CI: 7.1-8.5) in women. SMRs were substantially raised for deaths due to mental and behavioural disorders (men: 13.2, 95% CI: 12.3-14.0; women: 62.8, 95% CI: 52.7-74.9) and drug-related deaths (men: 12.8, 95% CI: 12.2-13.5; women: 50.3, 95% CI: 43.7-57.8). The SMR for death by homicide was 10.2 (95% CI: 8.9-11.7) in men and 26.3 (95% CI: 17.8-39.0) in women. Aboriginal men were 4.8 times, and Aboriginal women 12.6 times, more likely to die than the general NSW population. Over the study period on average all-cause SMR decreased significantly in men (p = 0.003) and women (p = 0.05) largely due to the decline in SMRs for drug-related deaths and suicide. CONCLUSION: In the largest study so far reported, mortality of male and female offenders was far greater than expected for all major causes, especially deaths caused by drug overdose. Despite some indication of a reduction in excess mortality in recent years, there remains an overwhelming need for enhanced responses to mental health and drug problems for people who have been in prison.

Transforming growth factor beta 1 production by CD4+ CD25+ regulatory T cells in peripheral blood mononuclear cells from healthy subjects stimulated with Leishmania guyanensis.

Transforming growth factor beta (TGF-beta) has been shown to be a central immunomodulator used by leishmaniae to escape effective mechanisms of protection in human and murine infections with these parasites. However, all the information is derived from studies of established infection, while little is known about TGF-beta production in response to Leishmania stimulation in healthy subjects. In this study, TGF-beta1 production was demonstrated in peripheral blood mononuclear cells from healthy subjects never exposed to leishmaniae in response to live Leishmania guyanensis, and the TGF-beta1-producing cells were described as a distinct subpopulation of CD4(+) CD25(+) regulatory T cells. The suppressive properties of CD4(+) CD25(+) T cells were demonstrated in vitro by their inhibition of production of interleukin 2 (IL-2) and IL-10 by CD4(+) CD25(-) T cells in the presence of either anti-CD3 or L. guyanensis. Although neutralization of TGF-beta1 did not reverse the suppressive activity of CD4(+) CD25(+) T cells activated by anti-CD3, it reversed the suppressive activity of CD4(+) CD25(+) T cells activated by L. guyanensis. Altogether our data demonstrated that TGF-beta1 is involved in the suppressive activity of L. guyanensis-stimulated CD4(+) CD25(+) T cells from healthy controls.

Mononuclear cells from patients recovered from cutaneous leishmaniasis respond to Leishmania major amastigote class I nuclease with a predominant Th1-like response.

The Leishmania major amastigote class I nuclease (LmaCIN) is a developmentally regulated protein that is highly expressed in the amastigote stage of L. major. This protein is homologous to the P4 nuclease of L. pifanoi, which has been shown to induce protective immune response in a murine model. To evaluate LmaCIN as a potential human vaccine candidate, cellular immune responses to recombinant LmaCIN were examined in individuals recovered from Old World cutaneous leishmaniasis. Peripheral blood mononuclear cells (PBMC) from patients recovered from L. major infection were cultured either with recombinant LmaCIN or autoclaved L. major (ALM) as control. rLmaCIN induced significant proliferation of PBMC from 90% of recovered patients. Phenotypic analysis of proliferating cells showed that CD8(+) cells were the predominant cell type proliferating in response to rLmaC1N. Screening of culture supernatants for cytokines showed that rLmaCIN induced high levels of interferon (IFN)-gamma (mean +/- s.e.m.: 1398 +/- 179 pg/ml) associated with little interleukin (IL)-10 and little or no IL-5 production. These findings show that LmaCIN is immunogenic in humans during L. major infection and that it can elicit immunological responses relevant to immunoprophylaxis of leishmaniasis.

Long-term immune and cytogenetic effects of high level natural radiation on Ramsar inhabitants in Iran.

Ramsar, a northern coastal city of Iran, overlooking the Caspian Sea, has some high level natural radiation areas (HLNRAs) as well as over 50 hot springs with low and high radium contents used as spas by the public and vacationers. The average whole body dose received by population in these areas is about 5 times higher than the normal background radiation level. Studies on the long-term effects of high level natural radioactivity on some immunological and cytogenetical parameters, in the Ramsar inhabitants are summarized in this paper. Our results showed a significant increase of CD69 expression on TCD4+ stimulated cells (P < 0.004) and a significant increase of total serum IgE (P < 0.05), and also higher incidence of stable and unstable chromosomal aberrations in the HLNRA group compared to the control group with normal background radiation (P < 0.05).Other humoral immune parameters, did not show significant differences between the two groups.

The self-reported health status of prisoners in New South Wales.

OBJECTIVE: To describe the physical health of the New South Wales prisoner population. DESIGN: Cross-sectional random sample of adult men and women prisoners. SETTING: 29 New South Wales correctional centres (27 male and two female). PARTICIPANTS: 747 men and 167 women. MAIN RESULTS: Despite the comparatively young population, 81% of women and 65% of men had at least one chronic health condition; 41% of men and 59% of women reported multiple health problems. The most common conditions were back problems, poor eyesight, arthritis, high blood pressure and asthma. Chronic conditions were more prevalent among women prisoners. Thirty-seven per cent of women and 28% of men rated their health as either 'poor' or 'fair' compared with 16% of women and 15% of men in the general NSW community. Psychiatric medication was more commonly prescribed to women than men (25% vs. 13%; p < 0.001). Similarly, methadone maintenance was more common among women than men (39% vs. 13%; p < 0.001). CONCLUSION: Men and women prisoners in NSW have multiple chronic health conditions. While not desirable, incarceration presents an opportunity to initiate treatment to improve the health of this disadvantaged group.

Increased production of interferon-gamma by Leishmania homologue of the mammalian receptor for activated C kinase-reactive CD4+ T cells among human blood mononuclear cells: an early marker of exposure to Leishmania?

A prospective study was undertaken to define early predictive immunological marker(s) of exposure to Leishmania in naïve subjects who have never been exposed to any Leishmania and who were also free of any cutaneous leishmaniasis lesions. These naïve subjects could have been exposed to Leishmania in a rain forest where Leishmania guyanensis and their natural vectors and mammalian host are cocirculating. The production of interferon (IFN)-gamma in response to the Leishmania homologue of the mammalian receptor for activated c kinase (LACK), a candidate for vaccine against leishmaniasis was analysed. At the end of their stay in the rain forest, LACK-specific CD8+ T cells were detected in subjects whose peripheral blood mononuclear cell (PBMC) produced IFN-gamma in response to soluble Leishmania antigens (SLA) and in those whose PBMC remained unresponsive to SLA. However, LACK-specific CD4+ T cells were detected only in PBMCs from individuals who became IFN-gamma responders to SLA. In subjects whose PBMC became positive to SLA, LACK-reactive CD4+ T cells producing high level of IFN-gamma were detectable before the SLA-reactive IFN-gamma producing CD4+ T cells, suggesting that the former readout assay could be used as an early predictive immunological marker of exposure to Leishmania in subjects who remained disease free.