Helminth Therapy: Advances in the use of Parasitic Worms Against Inflammatory Bowel Diseases and its Challenges.

Development of modern medicine and better living conditions in the 20th century helped in reducing a number of cases of infectious diseases. During the same time, expansion of autoimmunological disorders was noticed. Among other are Inflammatory Bowel Diseases (IBD) including ulcerative colitis and Crohn's disease which are chronic and relapsing inflammation of the gastrointestinal tract. Absence of effective treatment in standard therapies effects the search for alternative opportunities. As per hygienic hypothesis increasing number of cases of autoimmune diseases is as a result of reduced exposure to pathogens, especially parasites. Thus, one of the promising remedial acts against IBD and other allergic and autoimmune disorders is "helminth therapy". Cure with helminths seems to be the most effective therapy of IBD currently proposed. Helminth therapy focuses on advantageous results that have been obtained from the clinical trials, but its mechanisms are still unclear. Explanation of this phenomenon would help to develop new drugs against IBD based on helminth immunomodulatory molecules.

The intestinal nematode inhibits T-cell reactivity by targeting P-GP activity.

Host immunosuppression occurs during chronic nematode infection, partly due to effector T-cell hyporesponsiveness. The role of P-glycoprotein (P-gp), a member of the ABC transporter family, has been assessed in T-cell activity. This study assesses the possible role of P-gp in T-cell activity during nematode infection. Our findings indicate that blockade of P-gp in vivo increased protection against Heligmosomoides polygyrus nematode infection and was associated with the enhanced T-cell activity. Three P-gp-inhibitors, verapamil (VRP), cyclosporine (CsA) and tariquidar (XR9576), were used to determine the influence of nematode infection on the P-gp function of T cells. The influence of the nematode on the uptake, efflux and kinetics of extrusion in T-cell subsets CD4+ and CD8+ was assessed by the accumulation of Rho123 dye. The results indicate that H. polygyrus infection contributes to the inhibition of T-cell function by elevating P-gp activity. The blockade of P-gp in the T cells of infected mice led to an impressive increase in T-cell proliferation and IL-4 cytokine release through the upregulation of NF-κB activation. These results provide the first evidence that the P-gp function of T cells is altered during nematode infection to open the way for further studies aiming to explore the role of P-gp in host-parasite interactions.

The antiapoptotic activity of Heligmosomoides polygyrus antigen fractions.

Our study identified Heligmosomoides polygyrus antigen factors with potential activity for regulation of T-cell proliferation and surviving of CD4(+) CD25(-) , CD4(+) CD25(hi) and CD3(+) CD8(+) cell populations. The antiapoptotic activity of antigenic fractions separated by HPLC was evaluated in vitro after exposure of cells to DEX and rTNF-α. Different populations of cells responded to antigen fractions in distinct pattern; the most sensitive population of cells to H. polygyrus products were CD4(+) CD25(hi) after exposure to DEX and CD3(+) CD8(+) T cells after exposure to rTNF-α. H. polygyrus antigens may influence survival of CD8(+) T cells by regulation of c-FLIP rather than Bcl-2, which affects survival of CD4(+) CD25(hi) Treg cells and CD4(+) T cells. Activation of NF-κB subunits, for example, p50 and p65 was essential for resistance of cells to apoptosis, and antigenic fractions F9 and F17 exerted different effect to F13. The most active fraction in inhibition of apoptosis was F9, which includes Hsp-60, calumenin, ferritin, galectin and thrombospondin. This study may provide new clues for recognition of factors that regulate the immune response during infection and which engage the TNF-α receptor-mediated and the mitochondria-mediated death pathway.

Heligmosmoides polygyrus fourth stages induce protection against DSS-induced colitis and change opioid expression in the intestine.

Primary exposure of mice to the nematode Heligmosomoides polygyrus infection reduces inflammation in an experimental model of colitis. The aim of the present investigation was to evaluate whether the reduced inflammation provoked by H. polygyrus L4 larvae in BALB/c mice treated with dextran sulphate sodium is associated with changed expression of opioids in the small intestine and colon. Colitis was induced by 5% Dextran sulphate sodium (DSS) oral administration for 3 days before oral infection with 200 infective larvae (L3) H. polygyrus until the end of the experiment, 6 days post-infection. Clinical disease symptoms were monitored daily. The expressions of proopiomelanocortin POMC1, MOR1 (Oprm1) - opioid receptor and ß-endorphin were determined by RT-PCR, Western blot and immunoassay, respectively, in the colon and small intestine of mice. RT-PCR analysis of colon tissues showed up-regulation of the expression of POMC and MOR1 opioid-dependent genes in mice with DSS-induced colitis. H. polygyrus L4 larvae inhibited DSS-induced colitis symptoms that were correlated with increased IL-1ß, TNF-α, IL-6, myeloperoxidase (MPO) concentration, macrophages infiltration and MOR1, POMC and ß-endorphin increased expression in the small intestine and inhibition of those in the colon.