Final Report Summary - TH2MEMORY (Identification of key chemokine-chemokine receptor interactions that control the memory Th2 cells in allergic asthma)
Allergic asthma is a disease of airway inflammation caused by an allergic reaction to an antigen. Pathogenic CD4+ T helper type 2 (Th2) cells in lungs are involved in the initiation and perpetuation of the allergic response in airways of asthmatics and animals. To mimic disease in asthmatics, we developed a relapsing-remitting mouse model, in we investigate mice during remission and secondary antigen lung challenge induced relapses.
The factors governing the survival and retention of CD4+ Th2 cells in the lungs are unknown. The objectives of this project were to determine CKR expression on resting CD4+ T cells in the lungs during remission and correlate phenotype with effector function, to identify the critical CKR expression on Th2 cells allowing them to immigrate from the lung during antigen exposure; and to define antigen-specific Th2 cells.
To achieve our goals, we induced acute disease in mice and waited at least four months for recovery. We then compared chemokine and chemokine receptor expression in whole lungs from recovered and naive mice and in animals early in the course of their asthma attack by flow cytometry, realtime PCR and expression profiling.
We discovered that the levels of chemokine receptor gene expression does not distinguish lung memory cells in recovered mice. However, microarray data have revealed specific alterations in gene expression profiles between groups that are being further analysed. Several of these genes may be responsible for the long-lived character of CD4 Th2 memory cells in the lungs.
In an attempt to further delineate the nature of memory CD4 Th2 cells, we collaborated with two research groups at the Medical University of Vienna. In one study, we found that allergen-specific Th2 cell mediated lung inflammation was inhibited with a subcutaneous injection of a grass pollen mimotope peptide and in the second, we evaluated the ability of Th2 cell-mediated allergy in animals deficient in key epigenetic factors, thus addressing important mechanisms leading to the generation of Th2 memory cells.
The potential scientific impact of this project rests in the science and the socio-economic impact. The scientific impact of elucidation of the factors governing peripheral memory CD4 T and new treatment strategies will provide approaches to target CD4 T cells in immune mediated disease like asthma, autoimmune disease, cancer, transplantation, infectious diseases, especially parasitic, and vaccine development. The results from these studies will be included in manuscripts for publication in high impact journals.
The potential socioeconomic impact on elucidating the mechanisms underlying Th2 mediated immune diseases for patients with allergic and parasitic diseases is great. The high costs of health care associated with asthma and parasitic disease in Europe and Egypt can be considerably reduced when these diseases are treated. Infectious diseases are a strain on the well being of the people of Egypt and its health care system.
Dr El-housseiny has an interest in parasitic diseases that are a heavy financial burden on the economy. TH2MEMORY focused on a cell that plays a key role in parasitic and allergic diseases. This project might provide new mechanistic insights that will impact both diseases. The return of highly intelligent and talented medical scientists with specialty training abroad is an excellent strategy for the improvement of the health care system. The potential impact with Dr El-housseiny is the potential for beneficial co-operation between Europe and Egypt. She will return to her work with parasites. Target groups for whom the research could be relevant include medical universities, and medical research centres and allergic asthma interest groups, pharmaceutical companies and centres.
The factors governing the survival and retention of CD4+ Th2 cells in the lungs are unknown. The objectives of this project were to determine CKR expression on resting CD4+ T cells in the lungs during remission and correlate phenotype with effector function, to identify the critical CKR expression on Th2 cells allowing them to immigrate from the lung during antigen exposure; and to define antigen-specific Th2 cells.
To achieve our goals, we induced acute disease in mice and waited at least four months for recovery. We then compared chemokine and chemokine receptor expression in whole lungs from recovered and naive mice and in animals early in the course of their asthma attack by flow cytometry, realtime PCR and expression profiling.
We discovered that the levels of chemokine receptor gene expression does not distinguish lung memory cells in recovered mice. However, microarray data have revealed specific alterations in gene expression profiles between groups that are being further analysed. Several of these genes may be responsible for the long-lived character of CD4 Th2 memory cells in the lungs.
In an attempt to further delineate the nature of memory CD4 Th2 cells, we collaborated with two research groups at the Medical University of Vienna. In one study, we found that allergen-specific Th2 cell mediated lung inflammation was inhibited with a subcutaneous injection of a grass pollen mimotope peptide and in the second, we evaluated the ability of Th2 cell-mediated allergy in animals deficient in key epigenetic factors, thus addressing important mechanisms leading to the generation of Th2 memory cells.
The potential scientific impact of this project rests in the science and the socio-economic impact. The scientific impact of elucidation of the factors governing peripheral memory CD4 T and new treatment strategies will provide approaches to target CD4 T cells in immune mediated disease like asthma, autoimmune disease, cancer, transplantation, infectious diseases, especially parasitic, and vaccine development. The results from these studies will be included in manuscripts for publication in high impact journals.
The potential socioeconomic impact on elucidating the mechanisms underlying Th2 mediated immune diseases for patients with allergic and parasitic diseases is great. The high costs of health care associated with asthma and parasitic disease in Europe and Egypt can be considerably reduced when these diseases are treated. Infectious diseases are a strain on the well being of the people of Egypt and its health care system.
Dr El-housseiny has an interest in parasitic diseases that are a heavy financial burden on the economy. TH2MEMORY focused on a cell that plays a key role in parasitic and allergic diseases. This project might provide new mechanistic insights that will impact both diseases. The return of highly intelligent and talented medical scientists with specialty training abroad is an excellent strategy for the improvement of the health care system. The potential impact with Dr El-housseiny is the potential for beneficial co-operation between Europe and Egypt. She will return to her work with parasites. Target groups for whom the research could be relevant include medical universities, and medical research centres and allergic asthma interest groups, pharmaceutical companies and centres.