Immune responses to platelet can be threatening. Post-transfusion purpura (PTP) can result in serious bleeding in the affected individual. Neonatal alloimmune thrombocytopenia (NIAT) can harm the or the newborn. These disorders are based on the generation of alloantibodies by the transfusion recipient or by the mother of the affected infant. In general, the generation of any antibody by C cells requires T cell help. While the alloantibody response has been the subject of many studies, the role of T cells in the process has been relatively neglected. This omission need addressing as disabling T cell help could provide a way to control these disorders. In the previous funding period we have been developing novel approaches to study T cell responses and have been analyzing the role of T cells in thrombocytopenia. We have also utilized our expertise im immunogenetics to determine how peptides, derived from platelet proteins that are the targets of the response, could be interacting with the HLA-DR antigen presentation molecules. As a result of this previous work, we propose a model of clinically relevant alloimmunity that will be tested in this project. This model is composed of two hypotheses. The first proposes that the difference between the immunizing protein and the responder's self protein (often only one amino acid) controls both the B cell and T cell responses. The control of the B cell may be indirect as antibodies recognize overall shapes. The T cells will recognize the peptide that includes the polymorphism. The second hypothesis proposes that the difference between the alloantigen peptide that includes the polymorphism. The second hypothesis proposes that the difference between the alloantigen peptide and the corresponding self-peptide is one that allows the peptide to bind to the HLA-DR. This combination of peptides plus DR is the actual structure recognized by T cell receptor. The second hypothesis is based on our observations in one platelet alloantigen response and we generalize on this example. The rationale for this hypothesis is that by allowing the peptide to bind, the polymorphism has generated a new antigen that has not been previously seen by the immune system. This is in contract to the stimulation of the allopeptide having to overcome the tolerance induced by the immune system having been previously exposed to the similar self-peptide. If the corresponding self- peptide cannot bind, there is no tolerance to overcome. This project will test these two hypothesis for a number of platelet alloantigen systems as Aims 1 and 2 respectively.
In Aim 3, we propose to test, we propose to test these hypothesis by showing that we can control the parameters of the alloimmunization process and generate alloimmunity by controlled immunizations. As part of this aim, we will generate mice expressing one of the human alloantigen systems. This will enable us to manipulate the animals to further understand the variables important in alloimmunization during transfusion of pregnancy. Finally, because we will have identified the allogeneic peptides and antigen presentation molecules, we propose to modify the peptides to determine if it is feasible to induce T cell antagonism. The antagonism will be studied both in cultured T cells from NAIT or PTP cases, but also in the mouse model system. The knowledge gained from the studies described in this project can provide the basis for novel approaches to intervention in these disorders.
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