The Immunogenetics Program of the Department of Transfusion Medicine is focused on the identification of genetic variables that may influence the outcome of immunization protocols against cancer and in general against diseases that are prodominantly controlled by cellular immune responses. The Program includes two components: the Human Leukocyte Antigen (HLA) typing laboratory that is mainly covering the routine identification of known genetic variance among different populations through HLA molecular testing. In addition the HLA laboratory is going to more broadly apply immunogenetic profiling that includes typing of other immune relevant genes such as Killer Cell Immunoglobulin Like Receptors (KIR), Cytokines and FC-Receptors. The second component is the Immunogenetics Research Laboratory that includes a Functional Genomics Unit, a Proteomics Unit, a Single Nucleotide Polymorphism (SNP) detection unit, a pathogen chip detection unit and a T cell physiology unit. All of these units interact among them and with the HLA laboratory for the development of an integrated approach to the study of individual responses to immunological therapy aimed at the enhancement of adaptive or innate immune responses with special emphasis on cellular immune responses. Clinically, the Immunogenetics Program has developed in the last year two protocols. The first one is aimed at the recruitment of 30 Caucasian and 30 Chinese donors that will be tested for their immune responses to antigen (i.e. latent membrane protein-2 of the Epstein-Barr virus; LMP-2) or general pathogenic or therapeutic stimulation with lypopolysaccharide (LPS) or interleukin-2 (IL-2). Such responses will be confronted with the genetic backgrounds of the two populations by comparing changes in global transcript and protein expression with different genetic profiles that could be identified using a newly developed high-throughput oligonucleotide SNP detection chip. The hypothesis is that different ethnic backgrounds may modulate the response to general immune stimulators or antigen-specific responses in relation to differences in the ability of various genes to respond to stimulation. In addition, LMP-2 epitope mapping will be performed to see whether the notoriously different HLA phenotypes carried by the two populations will lead to differences in T cell responses to one of the immunogenic EBV proteins. This work will yield a global view of the possible influence that genetic background may have on disease predisposition, outcome and response of therapy in the context of immune responses. In particular, it may explain differences in individual responses to T cell-aimed immunizations. The second clinical protocol developed during the last year is aimed at the immunization of patients with Nasopharyngeal Cancer (NPC) at high risk of recurrence after local control of the primary. NPC is a cancer caused by EBV virus and highly dependent on the xpression of LMP-2. Previous work done by my group in the context of metastatic melanoma has convincingly shown that immunization of patients with cancer with protein products derived from proteins expressed by cancer cells can reproducibly induce strong T cell responses. These responses include the induction of large numbers of circulating CD8+ T cells capable of recognizing cancer cells in in vitro assays. However, the effectiveness of these cells in eradicating cancer in vivo remains disappointing. Improvements in clinical outcomes can be observed when immune stimulatory agents such as IL-2 are combined to the treatment. Therefore, with this protocol we will test whether: 1) immune responses can be elicited in patients with NPC using the LMP-2 protein from EBV that supposedly plays an oncogenic effect on the disease; 2) whether this responses may impact on recurrence rates; 3) estimate whether further studies are warranted to test whether the combination of immunestimulatory agents may enhance the frequency of clinical responses in patients with advanced NPC. In conclusion the Immunogenetics Program of the DTM, CC is devoted to the development and implementation of Translational Medicine efforts for the study of the immune responses in individuals of different ethnic backgrounds to active-specific immunization against cancer and other chronic conditions predominantly controlled by cellular immune responses.
Showing the most recent 10 out of 77 publications
