Over the past decade, high HLA epitope mismatch scores have been associated with inferior transplant outcomes using several tools, of which HLAMatchmaker is most well-known. This software uses... Show moreOver the past decade, high HLA epitope mismatch scores have been associated with inferior transplant outcomes using several tools, of which HLAMatchmaker is most well-known. This software uses theoretically defined polymorphic amino acid configurations, called eplets, for HLA compatibility analysis. Although consideration of eplet mismatch loads has potential for immunological risk stratification of transplant patients, the use of eplet matching in organ allocation algorithms is hindered by lacking knowledge of the immunogenicity of individual eplets, and the possibility that single mismatched amino acids, rather than complete eplets, are responsible for HLA antibody induction.There are several approaches to define eplet immunogenicity, such as antibody verification of individual eplets, and data-driven approaches using large datasets that correlate specific eplet mismatches to donor specific antibody formation or inferior transplant outcomes. Data-driven approaches can also be used to define whether single amino acid mismatches may be more informative than eplet mismatches for predicting HLA antibody induction.When using epitope knowledge for the assignment of unacceptable antigens, it important to realize that alleles sharing an eplet to which antibodies have formed are not automatically all unacceptable since multiple contact sites determine the binding strength and thus biological function and pathogenicity of an antibody, which may differ between reactive alleles.While the future looks bright for using HLA epitopes in clinical decision making, major steps need to be taken to make this a clinical reality.(c) 2021 The Author(s). Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). Show less
Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4(+) T cells recognizing... Show moreCeliac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4(+) T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences. Show less
Seasonal influenza epidemics lead to severe flu in 3 to 5 million individuals and emerging pandemic influenza strains pose an even greater threat to society. We describe a clinical trial in which... Show moreSeasonal influenza epidemics lead to severe flu in 3 to 5 million individuals and emerging pandemic influenza strains pose an even greater threat to society. We describe a clinical trial in which vaccine-specific responses were measured during two consecutive influenza seasons, including the season in which the 2009 pandemic virus emerged, and showed that these vaccines induced both humoral and cellular responses. However, these responses are unlikely to be protective against newly emerging strains, due to the variable nature of influenza virus. Therefore, the other chapters in this thesis describe concepts within peptide-based vaccination strategies, which is one method to induce responses to highly conserved sequences of influenza virus. We evaluated a concept based on long peptides directed to highly conserved B and T cell epitopes and showed that this vaccine was capable of inducing both humoral and cellular immune responses. Furthermore, the vaccine provided partial protection against infection in an animal model. We also described another successful strategy to enhance the immunogenicity of minimal peptides by modification of these peptides and proceeded with formulations to improve delivery of these minimal peptides. Altogether, the findings in this thesis may contribute to the development of the next generation influenza vaccines. Show less
The growing number of tuberculosis (TB) casualties urges development of not only more effective drugs and preventive vaccines but also development of post-exposure/therapeutic TB vaccines. Post... Show moreThe growing number of tuberculosis (TB) casualties urges development of not only more effective drugs and preventive vaccines but also development of post-exposure/therapeutic TB vaccines. Post-exposure/therapeutic TB vaccines are needed since 2 billion people worldwide harbor a latent Mycobacterium tuberculosis infection. This vast reservoir forms a major source of new TB cases: one out of every ten M. tuberculosis infected individuals will develop active TB disease at one point in life, while the remainder contains the bacilli without any clinical symptoms. The current vaccine, M. bovis BCG (BCG), is ineffective in already latently infected individuals. In a series of M. tuberculosis antigen discovery studies, aiming at identifying new M. tuberculosis biomarker- and vaccine antigens, we found that genes from the M. tuberculosis DosR regulon encode antigens that can induce specific T-cell immunity in M. tuberculosis infected individuals. We argue that these genes which are expressed by dormant and persisting bacilli may represent attractive targets for post-exposure/therapeutic vaccination against TB. This thesis focuses on the immunologic evaluation of these M. tuberculosis DosR encoded genes in humans and mice regarding immunogenicity, (latent) M. tuberculosis infection, induction of immune responses following BCG vaccination and exposure to environmental, non-tuberculous mycobacteria. Show less
