Training animal innate immune system to achieve a quicker immune response
For centuries, immunological memory was presumed to be exclusively carried out by the adaptive immune system, by which T and B cells were deemed to be solely capable of recognising an already seen pathogen. That's despite the fact that protection against reinfection has been reported in both plants and insects which lack adaptive immunity.
Recently, a growing body of literature has shown that innate immunity can be adapted after a first encounter with a pathogen, demonstrating an enhanced immune response to a second challenge. One of the molecules which is able to promote trained immunity is β-glucan.
Phileo by Lesaffre has developed a specific immune-training product, Safglucan®, to meet the challenge of teaching an animal's immune system to achieve a quicker response to immunological threats, while also helping vaccines to work better in the process.
Classical immunological memory
The action and efficiency of the immune system is essential to human and animal health, enabling the host body to protect itself against invading microbes. The immune system, which effectively operates as a host defence system, is made of several biological components, such as tissues and organs, immune cells and molecules. All these components work together to patrol the host body, with the task of identifying potential health threats, such as a virus, bacteria or parasite. Once the immune system has identified such a threat and distinguished it from the host body's own beneficial organisms, it works to eliminate the threat that is posed.
When a pathogen enters into a body, therefore, it is confronted by the body's innate immune system, operating as a first line of defence. This is made up of phagocytes (monocytes, macrophages, dendritic cells (DC) and neutrophils), complement proteins, antibodies and several small molecules (cytokines and chemokines).
The innate response develops quickly, triggering a defence mechanism to kill the invading pathogen, using the dendritic cells to process the pathogen by cutting it into small chunks of proteins (antigen). This action activates the adaptive cells and initiates an adaptive immune response.
While an adaptive response takes time to develop, it has the capacity to develop a defence memory which is antigen specific. This enables future attacks by the same antigen to be dealt with rapidly by way of a reactivation of the original defence mechanism. This process is called immunological memory and is used every day during a vaccination programme, based on the process of educating the immune response to be able to recognise a given pathogen.
Once the immune system has been suitably educated, it becomes more efficient in its response to reinfection than was previously possible.
In contrast to the classical immunological memory that requires gene rearrangement to generate the specificity and proliferation of antigen-specific lymphocytes clones, the increased responsiveness to secondary stimuli, resulting from trained immunity, is not specific to a particular pathogen. Trained immunity is mediated by the epigenetic remodelling of the chromatin, by the rewiring of certain metabolic pathways and by the functional reprogramming of phagocytes. This makes them more able to fight the next infection. In other words, exposing phagocytes to β-1,3 and 1,6 glucans leads to DNA level changes by allowing certain immune genes to be made more accessible for transcription. This leads, in turn, to an ability to produce more cytokines and respond faster to pathogens (fig1).
Figure 1 : Trained immunity model (Adapted from Goodridge, 2016. Nature Immunol Netea, 2017, Cell Host microbes)
Purified 1,3 and 1,6 β-glucans' immune training effects in animals
β-glucan is one of the molecules which has been shown to be able to train the innate immune memory. Indeed, Dectin 1, the receptors on innate immune cells, and phagocytes, specifically recognise β-glucans 1.3 and 1.6. The interaction between Dectin 1 and β-1,3 and 1,6 glucans lead to an immune activation of the phagocytes, allowing them to produce cytokines. One of the direct results of this interaction is the induction of trained immunity or innate immune memory in these phagocytes.
Figure 2: Structure of yeast β-glucans. Long chains of D-glucose molecules linked by the β-1,3 bond forming the backbones. The side chains are branched to the backbone by β-1,6 bond (Jan Raa, 2015).
Phileo, working in cooperation with the Veterinary School of Toulouse, selected Safglucan®, based on its mode of action in relation to immune cell models. Safglucan® is composed of a purified fraction of β-1,3/1,6 glucans extracted from a primary grown baker yeast strain (Saccharomyces cerevisiae) and a controlled process.
During the product's launch at Eurotier in 2018, Safglucan® was presented as having the ability to educate innate immune cells, enabling them to respond more efficiently to infections and potentiate vaccination more than was previously possible. In this context, animals which are vaccinated and supplemented with Safglucan® show higher antibody titres and a stronger ability to defend themselves against an invasive pathogen than is the case when Safglucan® isn't used.
Trained immunity leads to improved response to vaccination
The product's immuno-training qualities have been tested across many global trials with the results that have been achieved, enabling the company to state that Safglucan® supports the natural defences of a range of livestock species, while also helping to optimise the response to vaccination.
Phileo trials, run in China and Mexico with Safglucan®, for example, showed enhanced vaccine-induced immune responses against viral diseases in chicken.
The researchers involved in this work examined the immunostimulatory effect and adjuvant potential of β-1,3/1,6 glucans (Safglucan®) across several studies, where chicken were vaccinated against Newcastle Disease (ND). Safglucan® was administered either orally as a feed additive or parenterally together with the vaccine. Vaccinated and control birds were then challenged with a lethal dose of the ND virus two weeks post-vaccination and observed for about two weeks for morbidity and mortality. Blood samples were collected from the wing vein at different time points for humoral and cell mediated immunity assays (Fig. 3).
Figure 3: Antibody titers against NDV of birds from D1 to D35
The results showed that Safglucan® secured an increase in anti ND virus specific antibodies in the serum of supplemented chicken as compared to their vaccinated, but none-supplemented, counterparts. It was also shown that the product, administered parenterally together with the vaccine as an adjuvant, stimulated a 'strong and early antibody response' in chicken vaccinated with a killed vaccine against ND. It also induced a 'strong and long-lasting immune response' as compared to birds which were vaccinated, but without the addition of a β-1,3/1,6 glucans adjuvant.
All of which leads to the conclusion that Safglucan® is an important feed additive with the potential to help producers to reduce their use of antibiotics. Given in the right moment and with the appropriate dose, therefore, Safglucan® has the capacity to promote the innate immunity of farm animals.
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