Peptide - Based Immunotherapy for Food Allergy
5. Translation of PIT into Human Clinical Applications
treatment of allergic disorders. It is thus interesting to present some of the key results obtained. Several inhalant allergens have, indeed, been the object of PIT investigations: the major cat allergen Fel d 1, the bee venom allergen Api m 1 (Fellrath et al. 2003 ; Tarzi et al. 2006 ), and more recently the ragweed allergen Amb a 1 (Larch é 2007 ) and the dog aller- gen Can f 1 (Virtanen 2006 ). The most promising fi ndings were obtained with cat allergens, as evi- denced by studies completed in clinical settings (Larch é 2007 ). Administration of peptides contain- ing T - cell epitopes led to increased pulmonary functions in cat allergic patients and allowed exposure to cats with reduced symptoms (Maguire et al. 1999 ). In a double - blind placebo - controlled study, production of IL - 10 was increased in PBMC obtained from patients with cat allergic asthma after treatment with Fel d 1 peptides (Oldfi eld et al.
2002 ). Reduction in allergen - specifi c proliferative response as well as in the production of Th1 - biased and Th2 - biased cytokines was also observed. Co - culture experiments using PBMCs led to the isola- tion of CD4 + cells capable of actively suppressing allergen - specifi c proliferative responses of CD4 − cells obtained prior to peptide treatment (Verhoef et al. 2005 ). In the context of food allergy, it is reason- able to expect that similar phenomena may occur.
However, they may also differ on the basis of the differences between the sensitization mechanisms occurring at respiratory vs. intestinal mucosa.
5. Translation of PIT into Human
vaccines, illustrated by an impressive panel of ongoing preclinical and clinical trials (Purcell et al.
2007 ). Due to the recent progress in peptide chem- istry, it is no longer unrealistic to envisage the pro- duction of synthetic peptides at metric ton scale (Hampton 2005 ).
Besides automated peptide synthesis, plant - based expression systems have been suggested as novel methods for the large - scale production of peptide vaccines in the form of “ edible vaccine. ” Such an approach would address the stability issues associ- ated with the administration of peptides by oral route. T - cell epitopes of Japanese cedar pollen aller- gens, Cry j 1 and Cry j 2, were expressed in the edible part of transgenic rice, a staple food in Asian cultures (Hiroi and Takaiwa 2006 ). Effi ciency of the rice - based vaccine has shown promising results in mouse models, and whether such an approach is viable for the incorporation of food allergen T - cell epitopes would be interesting to explore.
5.3. Other Practical Issues
Several aspects related to the development of pep- tide - based vaccines warrant further investigation.
Route and frequency of administration ought to infl uence the outcome of the treatment. Parameters such as dose and volume, as well as the type of adjuvant (if any) classically determine the route and frequency of administration. With regard to doses, it has been proposed that doses of peptides fi t in a model where too low a dose would be insuffi cient to induce any biological response, and too high a dose would lead to activation of adverse effects (Larch é 2007 ). The same author also suggests that considerably higher doses of peptides are required to induce tolerance in murine systems and that the difference between mice and humans would stand around fi ve order of magnitude (Larch é 2001 ). And last, solubility, in vivo instability of synthetic pep- tides, and their short half - life are other issues that will need to be addressed.
6. Conclusion
Peptide - based immunotherapy has been praised as a promising strategy for food allergy by a number of of MHC molecules inherent to humans and the pro-
duction of peptides at an industrial scale, as well as other practical issues such as route of administration and optimal dose of peptides. These different aspects are the objects of the following section.
5.1. MHC Polymorphism
An epitope - based vaccine must be effective in a broad - range population, and must therefore take into account the MHC restriction of T - cell mediated immune response. Indeed, a highly desirable crite- rion is the design of peptides capable of inducing a tolerance response in individuals with different human leukocyte antigen (HLA) background. This hurdle may be overcome with the preparation of vac- cines containing multiple peptides that would be effective in binding various MHC molecules, thus effi cient in a larger MHC - heterogeneous population.
A second alternative would be the selection of those epitope sequences restricted to the HLAs that are most frequent in the human population. For example, there has been a report of unpublished observations suggesting that short regions of allergen sequence could comprise multiple overlapping HLA - binding motifs (Larch é and Wraith 2005 ). More interestingly, it was documented that the expression of seven alleles of HLA - DR — the most polymorphic HLA region in humans — was predominant in the Caucasian population: namely, DRB1 * 0101, DRB1 * 0301, DRB1 * 0401, DRB1 * 0701, DRB1 * 1101, DRB1 * 1301, and DRB1 * 1501. Thus, peptides that would effi ciently bind to these allele products would represent good PIT vaccine candidates (Texier et al.
2000 ).
5.2. Large - Scale Production of Peptides Peptide therapeutics is currently driven by the devel- opment of peptide - based vaccines for infectious diseases and tumors. In the United States, the peptide industry underwent a dramatic change in the past 5 years since the approval of the peptide drug Fuzeon (HIV - fusion inhibitor) by the U.S. Food and Drug Administration (FDA). A very recent review con- fi rmed this renewed enthusiasm for peptide - based
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reviews (Li and Sampson 2004 ; Sicherer and Sampson 2007 ; Burks et al. 2008a, 2008b ). While PIT investigations carried out with inhalant aller- gens have reached clinical settings with encouraging results, there is currently little information on the curative potential of PIT in food - induced allergies.
However, recent PIT investigations using murine models of food allergy — in particular, those recently generated in our laboratory — point the way toward promising avenues. Of the various strategies pro- posed, an immunotherapy based on the use of T - cell epitope - containing peptides has been, to date, the object of most investigations.
Elucidation of the mechanisms underlying PIT has guided research into further understanding of allergic responses, which may lead the way toward the design of more effi cient immunotherapeutic approaches. Mechanistically, the induction of events mediated by the class of regulatory T cells and key molecules such as IL - 10, TGF - β , and FOXP3 are actively researched. Clinical translation of PIT experimental data in the form of peptide - based “ vaccine ” for food allergy demands further investi- gation but is highly probable, and therapeutic trials in humans are eagerly awaited.
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