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      Abstract

      Hydrolyzed proteins are used worldwide in the therapeutic management of infants with allergic manifestations and have long been proposed as a dietetic measure to prevent allergy in at risk infants. The degree and method of hydrolysis, protein source and non-nitrogen components characterize different hydrolyzed formulas (HFs) and may determine clinical efficacy, tolerance and nutritional effects. Cow’s milk (CM)-based HFs are classified as extensively (eHF) or partially HF (pHF) based on the percentage of small peptides. One whey pHF has been shown to reduce atopic dermatitis in high-risk infants who are not exclusively breastfed. More studies are needed to determine the benefit of these formulas in the prevention of CM allergy (CMA) and in the general population. eHFs represent up to now the treatment of choice for most infants with CMA. However, new developments, such as an extensively hydrolyzed rice protein-based formula, could become alternative options if safety and nutritional and therapeutic efficacy are confirmed as this type of formula is less expensive. In some countries, an extensive soy hydrolysate is available.

      © 2016 Nestec Ltd., Vevey/S. Karger AG, Basel

      Introduction

      Atopic diseases and related health costs have dramatically increased in the last decades, and identification of the optimal approach for both prevention and treatment of allergy represents an important health priority.

Prevention of allergy and/or atopic disease is complex because different pre- and postnatal factors interfere with its expression, and are difficult to be fully identified and controlled. For the treatment of food allergies, guidelines recommend elimination of the culprit food allergen(s) [1-3] and, in cow’s milk (CM) allergy (CMA), the choice of an extensively hydrolyzed formula (eHF; with still small protein peptides) or an amino-acid-based formula is determined by the severity of the allergic manifestations, adverse reactions, acceptance, costs and availability of the formula. Whether a small amount of tolerated proteins in the diet facilitate acquisition of tolerance is still a matter of research. A recent study has shown that early introduction of peanuts modulated specific immune responses and significantly decreased the frequency of the development of peanut allergy among high-risk children [4].

      Cow’s Milk Allergy

CMA is, together with egg allergy, the most frequent food allergy in early childhood and affects 0.5-6% of infants [1, 5]. The incidence is determined by the type of feeding (breast- or formula fed) and the criteria of diagnosis (self-report or challenge proven) [1]. Symptoms of CMA are nonspecific, range from mild to severe and often involve different organs (e.g. the skin, respiratory and/or gastrointestinal tract and the systemic circulation), induce general manifestations (irritability, sleeping problems, poor growth or shock), and overlap with other disorders (i.e. gastroesophageal reflux disease) or functional conditions. A correct diagnosis may be challenging even for expert physicians, particularly in patients with negative IgE tests, but it is pivotal for an adequate management. Moreover, in the last years, an increased number of children is reported to be sensitized at the same time to different CM proteins (CMPs) and to other food allergens even during exclusive breastfeeding; with allergic manifestations occurring early in life due to an impaired development of oral tolerance [6].

      Cow’s Milk Proteins

CM presents two different fractions of proteins: casein (Cas) and whey proteins, both with allergenic properties. Whole Cas consists of four major proteins (αs1-, αs2-, β- and κ-Cas; Bos d 8) plus three γ-Cas deriving from the hydrolysis of β-Cas, namely γ1, γ2 and γ3. In whey, there are α-lactalbumin (α-Lac; Bos d 4) and β-lactoglobulin (β-Lg; Bos d 5), bovine serum albumin (BSA; Bos d 6), lactoferrin and immunoglobulins (Bos d 7) [7].

      Cas, β-Lg and α-Lac are considered major allergens, i.e. more than 50% of the individuals with CMA are sensitized to those proteins [7]. Some patients are only sensitized to minor proteins, which are present at very low concentrations in milk, such as BSA and lactoferrin [7]. Immunoreactive epitopes and peptide fragments of both β-Lg and Cas have been well characterized. Due to the relative resistance of β-Lg to acid hydrolysis and proteases, part of the protein remains intact and is absorbed as such.

The region of the major site of phosphorylation in bovine α- and β-Cas is strongly immunoreactive, resistant to digestive degradation and well conserved in other ruminant species (degree of sequence homology >80%), which explains cross-reactivity and allergic reactions in patients with CMA in case they consume ewe’s or goat’s milk as a substitute [8]. Milk allergenicity can be reduced by various processing methods but mainly by hydrolysis. Emerging knowledge of the immunogenicity of CMPs and peptides is of fundamental relevance for both patients and infant formula manufacturers to select and offer effective formulas for CMA.

      Hydrolyzed Formulas

      Many food allergens are stable and resistant to digestion by gastrointestinal enzymes or are digested into high molecular weight (MW) peptides which retain the IgE binding and T-cell-stimulating properties [7]. The molecular basis of alterations in allergenicity is the inactivation or destruction of epitopes. However, methods of CM processing should be carefully selected because they may even produce new epitopes (neotopes) or access hidden epitopes by denaturation of the native allergen (cryptotopes) [7].

Hydrolyzed formulas (HFs) differ according to the method, the timing and the degree of hydrolysis (i.e. intact protein molecules are broken down into peptides of various MW which have less allergenicity), the protein source (Cas, whey, rice or soy) and other nutritional components. The method of hydrolysis is critical for different allergens as heating denatures conformational epitopes (such as the ones of Cas and whey proteins), whilst glycation (nonenzymatic glycosylation) and lactic acid fermentation reduce allergenicity of α-Lac and β-Lg, specific enzymes act on sequential epitopes (from β-Lg), and ultrafiltration eliminates large proteins (such as β-Lg; table 1) [7]. Milk proteins in HFs are hydrolyzed using both specific industrial proteases, such as alcalase, pronase and papain, and gastrointestinal digestive enzymes, such as pepsin, trypsin and chymotrypsin, resulting in allergenic or bioactive peptides which can act differently from the intact native ones. The heating of proteins in the presence of reducing sugars produces the so-called Maillard reaction or glycation, which modifies milk proteins, their structure, aggregation and allergenic effect in different ways, which depend on the specific combination of proteins, sugars and temperature [7]. Cas and α-Lac are more heat stable than the whey proteins β-Lg and BSA. Heating milk at 120°C for 15 min did not alter the antigenicity of bovine Cas, but recognition of β-Lg by IgE was reduced by nearly 70% at 75°C whilst BSA and immunoglobulins lost their antigenicity at 70-100°C [9]. This could explain, at least partially, why some CMA patients are more tolerant to boiled milk than to raw milk. Processing at high temperatures

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