Filarial Abundant Larval Transcript Protein ALT-2: An Immunomodulatory Therapeutic Agent for Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) that accounts for about 5-10 % of all diabetes cases results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. It is characterized by severe inflammatory reaction mediated by pronounced T helper type-1 response. Parasitic infections having the ability to skew the host immune responses towards type-2 type as a part of their defense mechanism are able to induce protection against autoimmune diseases like T1D. Hence, the present study is undertaken to explore a recombinant abundant larval transcript protein of the human lymphatic filarial parasite Brugia malayi (rBmALT-2), a known anti-inflammatory molecule for its therapeutic effect on streptozotocin (STZ)-induced T1D in mice. The diabetic mice on treatment with rBmALT-2 showed a significant (p \ 0.0005) decrease in their fasting blood glucose levels. By the end of the second week after the initiation of treatment with the rBmALT-2, 28 % of the diabetic mice became normal and none of them were diabetic by the end of 5th week. The anti-diabetic effect of rBmALT-2 significantly correlated with the concomitant redressal of the pancreatic histopathological damage caused by STZ assault (rho = 0.87; p \ 0.0005).The sera of rBmALT-2 treated diabetic mice had increased levels of IgG1 antibodies associated with decreased IgG2a antibodies against the principal autoantigen insulin. The splenocyte proliferative response and the cytokine release in the treated mice showed marked bias against inflammation skewing the immune response to Th-2 type. From this study, it can be envisaged that that filarial proteins like rBmALT-2 with effective immunomodulatory activity and anti-diabetic effect are promising alternative therapeutic agents for T1D.

Therapeutic potential of the immunomodulatory proteins Wuchereria bancrofti L2 and Brugia malayi abundant larval transcript 2 against streptozotocin-induced type 1 diabetes in mice

“…In our earlier study (Reddy et al ., 2016) r Bm ALT-2 was found to be more effective in ameliorating T1D. By the end of the fifth week after initiating treatment, all the diabetic mice had turned to normal.…”

“…(2010) have shown that the T-cell epitopes of ALT2 from the filarial parasite Brugia malayi induce high levels of IL-10 secretions along with suppression of IFN-γ and IL-12 cytokines, suggesting their possible involvement in the modulation of the host immune system. In the earlier study from our laboratory, recombinant B. malayi abundant larval transcript 2 (r Bm ALT-2) with its effective immunomodulatory activity was shown to be a promising alternative therapeutic agent for T1D (Reddy et al ., 2016). Hence, in the present study, we have assessed and compared the curative effects of r Wb L2 and r Bm ALT-2 by administrating them individually and in combination to treat STZ-induced T1D in mice.…”

Recombinant antigens used as diagnostic tools for lymphatic filariasis

“…malayi endemic area [ 44 ]. Recombinant BmALT-1 and BmALT-2 have been evaluated as vaccine candidates [ 43 , 45 , 46 ], and the BmALT-2 immunomodulatory activity has been assessed as a prophylactic tool against diabetes induced by streptozotocin in mice [ 47 ].…”

Effects of helminths and anthelmintic treatment on cardiometabolic diseases and risk factors: A systematic review

“…In total, 29 studies compared baseline measures of diabetes or pancreatic inflammation in those with and without helminth infection. Seventeen studies (59%; 11 animal, 6 human) reported lower measures of diabetes or pancreatic inflammation [14,25,32,68,[72][73][74][75][76][77][78][79][80][81][82][83][84], 6 (21%; all human) demonstrated higher measures of these factors [6,[85][86][87][88][89], and 5 (17%; all human) showed no association with respect to helminth infections [53,58,59,71,90]. In the final study there was no difference in hemoglobin A1c or fasting glucose regardless of helminth infection or antiretroviral status among HIV-infected individuals, while among HIV-uninfected individuals, soil-transmitted helminth (STH) infection was inversely associated with hemoglobin A1c (5.2% vs. 5.5% in STH-uninfected controls) after adjustment for age and sex [69].…”

“…In comparison to the 6 human studies, 11 animal studies with mouse models using Schistosoma species (n = 7), Fasciola hepatica (n = 2), and filarial species (n = 2) also documented lower measures of diabetes or pancreatic inflammation among helminth-infected animals [72,[75][76][77][78][79][80][81][82][83][84]. Seven of 11 documented histopathological changes of the pancreas in mice and found that helminth infection was associated with less pancreatic inflammation, degradation, and other architectural changes in mice who were infected or exposed to helminth antigens as compared to uninfected mice [72,[76][77][78][79][80][81]. These studies also documented a lower incidence of diabetes between infected and uninfected mice, and via correlations with pancreatic histopathological changes suggested helminths may possibly protect against autoimmune diabetes.…”