Jan Peter Dutz
Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Mar 2019)
Vaccination is a cost-effective method to prevent diseases. Yet, vaccine effectivenessremains lower than anticipated and infectious disease is still a leading cause of illness and death.Immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG ODNs) activate Tolllikereceptor 9 (TLR9), bridging innate and adaptive immune responses. CpG ODNs have beenstudied as adjuvants, agents to improve vaccine efficacy. However, split administration of topicalTLR9 agonists with parenteral vaccines has been less explored. I hypothesized that topical CpGODN 1826 activates the skin immune system in a unique fashion, increasing the efficacy oflocally administered protein-based vaccines. I found that an effective strategy to administer CpGODN was single dose topically at time of local parenteral vaccine delivery. The generation ofantigen-specific antibodies, CD4⁺ T helper 1 cells and CD8⁺ T cells were augmented. In murineListeria monocytogenes and influenza A infection models, application of topical CpG ODN attime of parenteral protein immunization reduced bacterial and viral burden.The mechanisms whereby topical CpG adjuvant improves vaccine outcomes wereinvestigated. Using bone marrow chimeric mice, I found that TLR9 expression in thehematopoietic compartment was necessary while expression in the stromal compartment alsocontributed to the enhancement of specific CD8⁺ T cell generation. Keratinocytes responded totopical CpG ODN partly by up-regulating TLR9 expression. Topical CpG ODNs wereinternalized by CD11c⁺ cells and were detected within the skin draining lymph nodes (SLNs).Topical compared to subcutaneous administration of CpG ODN differentially modulatedcytokine and chemokine gene expressions in the SLNs and induced a higher proportion of specific CD4⁺ T cells to express tissue-homing molecules. In the influenza model, topical CpGadjuvant increased the proportion of specific CD8⁺ memory T cells at the site of infection.This work demonstrates the effectiveness of a novel immunization strategy that separates topicalCpG adjuvant from a protein-based vaccine in enhancing rapid and long-lasting protectivehumoral and cellular vaccine responses. These improved responses are the consequences of theactivation of stromal and hematopoietic cells in the skin, which subsequently modulate themicroenvironment of the SLNs and alter the migratory ability of the T cells to tissues.
Master's Student Supervision (2010-2017)
Introduction: Psoriasis (PsC) and psoriatic arthritis (PsA) represent common, lifelong inflammatory diseases of the skin and joints (respectively) with substantial cardiovascular morbidity. Considering the important deleterious impact that depression can have on disease complications and long-term health outcomes, we investigated the population burden of physician-diagnosed depression among individuals with PsC and PsA and the potential long-term impact of depression on acute myocardial infarction (AMI) risk in this patient population. Objectives: 1) To evaluate the incidence and prevalence of depression in the context of PsC and PsA; 2) To compare the odds of depression among individuals with PsC and PsA to healthy controls; 3) To determine whether depression is an independent risk factor for AMI in PsC and PsA; and 4) To determine whether depression modifies the risk of AMI associated with PsC and PsA. Methods: Epidemiologic methods were used to address Objectives 1-4 based on population-based cohorts of PsC and PsA patients compared to age-, sex-, and index date-matched controls. Results: 1) The incidence of depression among individuals with PsC and PsA was 3.35 per 1,000 person-years (PY) and the corresponding prevalence during a mean observation period of 4.8 years was 24.63%; 2) There was a 16% increased odds of depression among individuals with PsC and PsA compared to controls; 3) Incident depression increased the risk of incident AMI by 75% in PsC and PsA, and; 4) An increased risk of AMI among individuals with PsC and PsA was observed among individuals with prevalent depression (i.e., depression modified the effect). Conclusion: These population-based data provide evidence for a substantial burden and increased odds of depression in PsC and PsA compared to controls. Depression was observed to be an independent risk factor for AMI among patients with PsC and PsA. Moreover, depression acted as an effect modifier for AMI in the context of PsC and PsA, such that PsC and PsA only led to an increased risk of AMI among individuals with depression. These data underscore the need to actively screen for depression among PsC and PsA patients and closely monitor cardiovascular health in this high-risk group to improve long-term survival.