title: Haemophilia management: time to get personal?
abstract: The possibility of alloimmunization in patients receiving protein replacement therapy depends on (at least) three risk factors, which are necessary concomitantly but insufficient alone. The first is the degree of structural difference between the therapeutic protein and the patient's own endogenous protein, if expressed. Such differences depend on the nature of the disease mutation and the pre-mutation endogenous protein structure as well as on post-translational changes and sequence-engineered alterations in the therapeutic protein. Genetic variations in the recipients' immune systems comprise the second set of risk determinants for deleterious immune responses. For example, the limited repertoire of MHC class II isomers encoded by a given person's collection of HLA genes may or may not be able to present a 'foreign' peptide(s) produced from the therapeutic protein - following its internalization and proteolytic processing - on the surface of their antigen-presenting cells (APCs). The third (and least characterized) variable is the presence or absence of immunologic 'danger signals' during the display of foreign-peptide/MHC-complexes on APCs. A choice between existing therapeutic products or the manufacture of new proteins, which may be less immunogenic in some patients or patient populations, may require prior definition of the first two of these variables. This leads then to the possibility of developing personalized therapies for disorders due to genetic deficiencies in endogenous proteins, such as haemophilia A and B. [Correction made after online publication 11 July 2011: several critical corrections have been made to the abstract].
authors.affiliation: Department of Pathology and Laboratory Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. tom.howard@va.gov
authors.forename: T E
authors.initials: TE
authors.lastname: Howard
authors.forename: C
authors.initials: C
authors.lastname: Yanover
authors.forename: J
authors.initials: J
authors.lastname: Mahlangu
authors.forename: A
authors.initials: A
authors.lastname: Krause
authors.forename: K R
authors.initials: KR
authors.lastname: Viel
authors.forename: C K
authors.initials: CK
authors.lastname: Kasper
authors.forename: K P
authors.initials: KP
authors.lastname: Pratt
mesh_terms: D017850:Economics, Pharmaceutical; D005169:Factor VIII / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007518:Isoantibodies / Q000276:immunology; D012307:Risk Factors
chemical_list: D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies; D005169:Factor VIII