Immune Activation at Effector and Gene Expression Levels After Measles Vaccination in Healthy Individuals: A Pilot Study Neelam Dhiman, Inna G. Ovsyannikova, Ann L. Oberg, Diane E. Grill, Robert M. Jacobson, and Gregory A. Poland ABSTRACT: Cellular immunity to measles vaccination is not fully understood at the effector response and gene expression levels. We enrolled 15 healthy individuals (15–25 years old) previously vaccinated with two doses of measles-mumps-rubella-II vaccine to characterize their cellular immunity. We detected a spectrum of lymphoproliferative response (median stimulation indi- ces of 3.4), low precursor frequencies of interferon- (median 0.11%) and interleukin-4 (median 0.05%) by Elispot, and cosecretion of Th1 and Th2 cytokines after measles virus stimulation. Further, global gene expres- sion was examined in five subjects from this cohort after vaccination with an additional dose of measles vaccine (Attenuax, Merck) to identify the genes involved in measles immunity. Linear mixed effect models were used to identify genes significantly up or downregulated in vivo between baseline and Days 7 and 14 after measles vaccination. Measles vaccination induced upregulation of a set of 80 genes, which play a role in measles immunity, signal transduction, apoptosis, cell proliferation, and met- abolic pathways. Among the 34 genes that were down- regulated, only interferon- is known to have a direct role in measles immunity. This study suggests that measles vaccination leads to activation of multiple cellular mech- anisms that can override the immunosuppressant effects of the measles virus and induce immunity. Human Immu- nology 66, 1125–1136 (2005). © American Society for Histocompatibility and Immunogenetics, 2006. Pub- lished by Elsevier Inc. KEYWORDS: Measles; microarray; gene expression; cy- tokines ABBREVIATIONS Bcl-2 B-cell lymphoma-2 CIITA class II transactivator EIA enzyme immunoassay IFN- interferon-alpha IL-1 interleukin-1 alpha MMR-II measles-mumps-rubella II PBMC peripheral blood mononuclear cells PBS phosphate buffered saline PHA phytohemagglutinin INTRODUCTION Measles remains a significant health issue in pediatric populations, despite the availability of an effective two- dose measles-mumps-rubella-II (MMR-II) vaccine [1,2]. The development of improved vaccination strategies to prevent measles can be guided by an understanding of the complex immune mechanisms that play a role in effective vaccination. Measles infection, and to a lesser degree measles vacci- nation, leads to a generalized immunosuppression mani- fested as decreased lymphoproliferative response to mito- gens, depressed skin sensitivity to recall antigens, and increased susceptibility to secondary infections [3–7]. Host responses evaluated after measles vaccination or infection also demonstrate a disturbed cytokine milieu, favoring a Th2 cytokine polarization [4,7–9]. It has been demon- From the Mayo Vaccine Research Group (N.D., I.G.O., R.M.J., G.A.P.), Division of Biostatistics (A.L.O., D.E.G.), and Department of Pediatric and Adolescent Medicine (R.M.J.), Program in Translational Immunovirology and Biodefense (G.A.P.), Mayo Clinic College of Medicine, Rochester, MN. Address reprint requests to: Gregory A. Poland, MD, Mayo Vaccine Research Group, Mayo Clinic and Foundation, 611C Guggenheim Build- ing, 200 First Street SW, Rochester, MN 55905. E-mail: poland.gregory@ mayo.edu. Received May 18, 2005; accepted September 29, 2005. Human Immunology 66, 1125–1136 (2005) © American Society for Histocompatibility and Immunogenetics, 2006 0198-8859/05/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2005.10.002