Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis.

In the months that follow autologous hematopoietic stem cell transplantation (AHSCT), lymphopenia drives homeostatic proliferation, leading to oligoclonal expansion of residual cells. Here we evaluated how replicative senescent and exhausted cells associated with clinical outcomes of 25 systemic sclerosis (SSc) patients who underwent AHSCT. Patients were clinically monitored for skin (modified Rodnan's skin score, mRSS) and internal organ involvement and had blood samples collected before and semiannually, until 3 years post-AHSCT, for quantification of telomere length, CD8+CD28- and PD-1+ cells, and serum cytokines. Patients were retrospectively classified as responders (n = 19) and non-responders (n = 6), according to clinical outcomes. At 6 months post-AHSCT, mRSS decreased (P < 0.001) and the pulmonary function stabilized, when compared with pre-transplant measures. In parallel, inflammatory cytokine (IL-6 and IL-1ß) levels and telomere lengths decreased, whereas PD-1 expression on T-cells and the number of CD8+CD28- cells expressing CD57 and FoxP3 increased. After AHSCT, responder patients presented higher PD-1 expression on T- (P < 0.05) and B- (P < 0.01) cells, and lower TGF-ß, IL-6, G-CSF (P < 0.01), and IL-1ß, IL-17A, MIP-1α, and IL-12 (P < 0.05) levels than non-responders. Homeostatic proliferation after AHSCT results in transient telomere attrition and increased numbers of senescent and exhausted cells. High PD-1 expression is associated with better clinical outcomes after AHSCT.

Immunomodulatory effects of aqueous and organic fractions from Petiveria alliacea on human dendritic cells.

Petiveria alliacea is a plant traditionally known for its anti-inflammatory and anti-tumor activities; however, the molecular and cellular mechanisms of its immunomodulatory properties are still unknown. Dendritic cells (DC) promote adaptive immune response by activating T lymphocytes, inducing an effector response or tolerance depending on the DC differentiation level. Herein, we evaluated the immunomodulatory activity of aqueous and organic plant fractions from P. alliacea using human monocyte-derived dendritic cells. The phenotype, cytokine secretion and gene expression were estimated after treatment with the plant fractions. We found that P. alliacea aqueous fraction induced morphological changes and co-stimulatory expression of CD86, indicating partial DC maturation. In addition, pro-inflammatory cytokines such as IL-1ß, IL-6, IL-8, IL-10, IL-12p70, and TNF-α were secreted. The fraction also increased NF-κB gene expression while down-regulating TGFß gene expression. These results suggest that the aqueous fraction can induce partial DC activation, a situation that can be relevant in tolerance induction. It is important to state that the organic fraction by itself does not show any immunomodulatory activity. This study provides evidence for possible immunomodulatory activity of P. alliacea extracts which has been used in traditional medicine in Colombia.

Identification of multiple HLA-A*0201-restricted cruzipain and FL-160 CD8+ epitopes recognized by T cells from chronically Trypanosoma cruzi-infected patients.

Chronic Chagas disease occurs in 16 million individuals chronically infected by the protozoan Trypanosoma cruzi in Latin America, and may lead to a dilated cardiomyopathy in 10-30% of patients. A vigorous cellular immune response holds parasitism in check. However, up to now, few T. cruzi proteins have been shown to be recognized by CD8+ T cells from Chagas disease patients. In this study, we designed 94 peptides derived from T. cruzi proteins cruzipain and FL-160, predicted to bind to HLA-A2 molcules. After in vitro binding assays to HLA-A*0201, 26 peptides were selected, and their recognition by PBMC from Chagas disease patients was tested with the IFN-gamma ELISPOT assay. All 26 peptides were recognized by PBMC from at least one patient. Furthermore, a tetrameric HLA-A*0201 complex built with the cruzipain 60-68 peptide that was frequently recognized in the periphery also bound to CD8+ T cells from a heart-infiltrating T cell line obtained from a single patient with Chagas disease cardiomyopathy. Thus, our results suggest that the recognition of CD8+ T cell epitopes in cruzipain and FL-160 may have a pathogenic or protective role in chronic Chagas disease.