Cytomegalovirus (CMV) infections remain a serious problem in hematopoietic stem cell transplant patients. Following transplantation CMV infections can cause peumonititis, hepatitis, enteritis, and marrow failure. CMV seropositive transplant recipients can be treated with antiviral agents such as ganciclovir at the onset of infection or at the time of stem cell engraphment, but ganciclovir therapy is associated with renal toxicity and suppression of neutrophil counts. Preliminary studies have found that adoptive immune therapy using CMV-reactive cytotoxic T lymphocytes (CTL) may be an effective and less toxic alternative to prevent CMV infection in seropositive recipients of marrow transplants. The purpose of this study is to develop new treatment strategies for producing CMV-reactive CTLs that can be used for adoptive immunetherapy and to better understand the cellular immune response to CMV. Current studies are focused on identifying the immune dominant peptides that can be used to stimulate CMV reactive CTLs. CMV contains over 200 proteins, but one protein, pp65, is the most immunogenic. Within pp65, CTLs from HLA-A*0201 people recognize only a single peptide, a nanomer pp65 495-503. We have found that for HLA-A*2402 people the immune dominant peptide is pp65 328-337. We have found that peptide pp65 341-350 is immune dominant for HLA-A*0101 and HLA-A*2402 and pp65 91-100 is immune dominant for the antigen HLA-A*3301 and important Asian allele. In contrast, among individuals expressing HLA-A*03 there was no single immune dominant peptide. Instead, three different pp65 peptides appear to be immune dominant in different subsets of HLA-A*03 individuals. We have also begun collaborative studies with Drs. John Barrett and Scott Solomon of the NHLBI. They are planning to vaccinate hematopoietic stem cell donors with a canary pox vector containing the gene for CMV proteins pp65 and IEP prior to the collection and transplantation of stem cells. We will be monitoring the donor's immune response to the vaccination. In a pilot study we found that it is possible to monitor the immune response to CMV by stimulating lymphocytes with pools of peptides 15 amino acids in length that over lap at 4 amino acids and measuring intracellular production of interferon-gamma.
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