2003; baxter - Supplements - Haematologica

[Immunobiology of Tolerance Induction]review paperT-lymphocytes in the anti-factorVIII immune responsehaematologica 2003; 88(suppl. n. 12):64-65http://www.haematologica.org/free/immunotolerance2001.pdfMARC G. JACQUEMIN, JEANMARIE R. SAINT-REMYCenter for Molecular and Vascular Biology, Universityof Leuven, BelgiumThe immune response towards factor VIII(FVIII), as for any other soluble glycoprotein,requires the participation of B- and T-lymphocytes. In the absence of specific T-cells nohelp is provided to B-cells to allow them tomature and differentiate into antibody secretingcells. Somewhat surprisingly, the involvement ofT-cells has been more or less neglected by mostinvestigators, when at the same time most effortwas been devoted to the characterization of B-cell epitopes and antibodies.Why is it so important to characterize specificanti-FVIII T-cells? First of all, T-cell recognitionof an antigen is the first specific event in themounting of an immune response. When anantigen enters the body, it has to be taken up bycells specialized in the presentation of it. Thisinvolves the intracellular digestion of the proteinfollowed by presentation of short peptidesderived from the digestion in the context ofMHC-class II molecules. The T-cell makes thefirst specific reading of the antigen, i.e. peptidebound to MHC class II alleles, which allows it tobecome activated and to provide B-cells with thehelp necessary for activation and the productionof antibodies.Second, T-cells recognize the peptide derivedfrom the antigen only when it is presented in theappropriate MHC class II molecule. This restrictionmakes it plausible that some alleles of MHCclass II molecules are preferentially associatedwith FVIII peptides. Therefore, it can be assumedon a theoretical basis that the capacity to produceinhibitor antibodies is associated with theexpression of a particular set of class II molecules.If so, this could represent a means to identifypatients at risk of producing inhibitory antibodies.Third, T-cells could represent an ideal target forthe design of an immunotherapy for FVIIIinhibitors. This is inherent to the actual characteristicsof the T-cell repertoire. T-cells are producedby the bone marrow, but must proceedthrough the thymus to acquire full maturation.The T-cell pool is essentially acquired at birth andmost of the thymus function disappears duringinfancy. Besides, the mechanism of somatichypermutation, which is responsible for a largeCorrespondence: JeanMarie R. Saint-Remy, Center for Molecularand Vascular Biology, University of Leuven, Belgium.E-mail: jeanmarie.saint-remy@med.kuleuven.ac.bepart of the diversity of B-cells, does not play arole at the level of T-cells. Controlling the T-cellarm of the anti-FVIII immune response could,therefore, result in a long-standing state of unresponsiveness.One caveat is however that the sizeof the T-cell repertoire is such that it has thecapacity to respond to any imaginable T-cell epitopein the universe. FVIII being a large molecule,it should always be possible to find a T-cellreacting towards it.Evidence for T-cell involvement in theanti-FVIII immune responseThe evidence is two-fold. In animal models,and in particular in the hemophilia A mousemodel, specific T-cells are already observed 3 daysafter the first administration of FVIII, well beforethe first antibodies can be detected. 1 It is alsoknown in such models that an interruption inthe B – T-cell dialog by, for instance, antibodiesto a surface molecule such as CD40L expressedon T-cells, prevents the development of theresponse. The second series of data comes fromobservations made in patients. A few years ago itwas observed that in HIV infected patients thetiter of anti-FVIII inhibitors declined togetherwith the number of CD4 + T-cells. 2More direct evidence has been obtained in manthrough the demonstration of FVIII-reactive T-cells in the peripheral blood of hemophilia Apatients with inhibitors. More recently, a veryexhaustive investigation was carried out using alarge number of synthetic peptides covering theentire FVIII sequence. These peptides were incubatedwith peripheral blood T-cells of hemophiliaA patients with or without inhibitors. A largenumber of FVIII peptides activating CD4 + T-cellswere found. However, screening hemophilia Apatients without inhibitor and healthy individualsas controls, it was found that individuals withnormal levels of FVIII also had specific T-cells intheir circulation. 3The latter observation raised questions aboutthe meaning of these findings. In vivo, theimmune system is confronted by full proteins andnot by peptides derived from them. T cell epitopeson a protein are organized according to a hierarchy.Major epitopes are dominant in the sensethat they are recognized by the large number andas a first line of recognition; these are also theepitopes towards which tolerance is establishedby selective deletion in the thymus. Minor epitopesare recognized less predominantly and oftenhaematologica vol. 88(supplement n. 12):september 2003