Mary S. Hayney

IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpastures syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

Factors influencing decisions regarding influenza vaccination and treatment: a survey of healthcare workers.

Surveys conducted in our healthcare facility evaluated factors associated with acceptance of influenza vaccination and opinions regarding influenza prevention and treatment and willingness to pay. Avoiding lost work and low risk were primary reasons for vaccine recipients and non-recipients, respectively. One-third of vaccine recipients would refuse vaccination if asked to pay at least

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

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Meditation or Exercise for Preventing Acute Respiratory Infection: A Randomized Controlled Trial

RATIONALE The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation. OBJECTIVES To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. METHODS Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa(O(2))/Fi(O(2)) index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. MEASUREMENTS AND MAIN RESULTS We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4(+) T-cell and monocyte mediated, and dependent on IL-17, IL-1beta, and tumor necrosis factor (TNF)-alpha. Pa(O(2))/Fi(O(2)) indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa(O(2))/Fi(O(2)), increased local TNF-alpha and IL-1beta production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts. CONCLUSIONS The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.

Immunization Recommendations for Adults with Cancer

PURPOSE This study was designed to evaluate potential preventive effects of meditation or exercise on incidence, duration, and severity of acute respiratory infection (ARI) illness. METHODS Community-recruited adults aged 50 years and older were randomized to 1 of 3 study groups: 8-week training in mindfulness meditation, matched 8-week training in moderate-intensity sustained exercise, or observational control. The primary outcome was area-under-the-curve global illness severity during a single cold and influenza season, using the Wisconsin Upper Respiratory Symptom Survey (WURSS-24) to assess severity. Health care visits and days of missed work were counted. Nasal wash collected during ARI illness was assayed for neutrophils, interleukin-8, and viral nucleic acid. RESULTS Of 154 adults randomized into the study, 149 completed the trial (82% female, 94% white, mean age 59.3 ± 6.6 years). There were 27 ARI episodes and 257 days of ARI illness in the meditation group (n = 51), 26 episodes and 241 illness days in the exercise group (n = 47), and 40 episodes and 453 days in the control group (n = 51). Mean global severity was 144 for meditation, 248 for exercise, and 358 for control. Compared with control, global severity was significantly lower for meditation (P = .004). Both global severity and total days of illness (duration) trended toward being lower for the exercise group (P=.16 and P=.032, respectively), as did illness duration for the meditation group (P=.034). Adjusting for covariates using zero-inflated multivariate regression models gave similar results. There were 67 ARI-related days of-work missed in the control group, 32 in the exercise group (P = .041), and 16 in the meditation group (P <.001). Health care visits did not differ significantly. Viruses were identified in 54% of samples from meditation, 42% from exercise, and 54% from control groups. Neutrophil count and interleukin-8 levels were similar among intervention groups. CONCLUSIONS Training in meditation or exercise may be effective in reducing ARI illness burden.

Polymorphisms of the TAP2 gene may influence antibody response to live measles vaccine virus

OBJECTIVE: To review the published literature on immunizing nonbone marrow transplant adult cancer patients, summarize the findings, and make recommendations for the use of vaccines in this population. DATA SOURCE: A search of MEDLINE and CancerLit was conducted (1966–June 2001) to find English-language clinical studies and review articles pertaining to immunization, vaccines, and cancer in humans. Recommendations of the Advisory Committee on Immunization Practices were used extensively. References of each identified article were subsequently reviewed for additional relevant articles. STUDY SELECTION AND DATA EXTRACTION: Representative epidemiologic reports, clinical trials, and recommendations of expert panels are summarized in this report. Relevant information was selected to describe the epidemiology of vaccine-preventable diseases, efficacy of the vaccines, and recommendations specific to adults with cancer. DATA SYNTHESIS: In general, adults with cancer are at least at the same risk of infection with vaccine-preventable diseases as are healthy populations. Because of their compromised immune function, many patients who have undergone cancer treatment are specifically at increased risk of morbidity and mortality associated with measles and varicella infections. Asplenic patients with lymphoma are at increased risk of fulminant bacterial infections. Influenza infection is associated with significant morbidity in cancer patients. Although the protection conferred by immunization is lower in immunosuppressed patients with cancer, immunization with inactivated vaccines is indicated. Live vaccines should not be used except in very rare instances. CONCLUSIONS: Immunization of adults with cancer is a critical component of their care. Although additional research is necessary, following established recommendations may protect individuals with malignancies from significant morbidity and mortality associated with vaccine-preventable diseases.

Relationship of HLA-DQAI alleles and humoral antibody following measles vaccination

The transporter associated with antigen processing (TAP) gene products transport peptides from the cytosol to the endoplasmic reticulum for processing by the immune system. We hypothesized that polymorphisms within the TAP genes may influence measles vaccine antigen processing and hence antibody response. TAP genotypes were determined for subjects who were measles vaccine nonresponders (n = 32) and hyper-responders (n = 28). TAP1 and TAP2 alleles were determined by PCR amplification of specific alleles (PASA). Measles vaccine nonresponders were more likely to be homozygous at TAP2 position 665 than were hyper-responders (OR = 5.0, P = 0.016). Lastly, a trend was found in the overall distribution of all TAP2 genotype frequencies between hyper-responders and nonresponders (P = 0.08). No association was found between TAP1 polymorphisms and vaccine response. These data reveal an association between TAP2 genotype and measles vaccine antibody response which may explain one mechanism behind vaccine failure.

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND The human leukocyte antigen (HLA)-DQA1 locus is only moderately polymorphic compared to other HLA class II loci; however, we hypothesized that these polymorphisms could be important in determining the humoral antibody response to measles vaccine virus. METHODS The seroprevalence of measles antibody was determined in 881 school children who had been immunized with MMR-II at age approximately 15 months. All subjects resided in a geographic area with no circulating measles virus. The IgG antibody levels were determined by a measles-specific whole virus enzyme immunoassay (EIA) (BioWhittaker, Walkersville, MD). Subjects who were nonresponders (IgG seronegative or equivocal) (n = 46) and hyperresponders (upper 10th percentile of IgG levels of all subjects) (n = 64) were HLA-DQA1 typed using polymerase chain reaction with sequence-specific primers (PCR-SSP). The HLA-DQA1 allele frequencies, as well as homozygosity rates, were compared between the nonresponders and hyperresponders. RESULTS The overall allele frequency distribution of alleles between the nonresponders and hyperresponders was significantly different (P = 0.05), with nonresponders having an excess of HLA-DQA1*05 alleles (P = 0.017) and hyperresponders having an excess of HLA-DQA1*01 alleles (P = 0. 016). The homozygosity rate among nonresponders was significantly higher than among hyperresponders (23.9% vs. 9.4%, P = 0.037). CONCLUSION HLA-DQA1 alleles have important associations with the antibody response to measles vaccine. Specifically, the carriage of the HLA-DQA1*05 alleles is associated with nonresponse and that of HLA-DQA1*01 alleles with hyperresponse. In addition, HLA-DQA1 homozygosity is significantly associated with poor antibody response to measles vaccine.

The association between psychosocial factors and vaccine-induced cytokine production☆

OBJECTIVES Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. METHODS Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. CONCLUSIONS It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.

Perceptions of pharmacy students, faculty members, and administrators on the use of technology in the classroom.

Existing data suggest that immune function is compromised by negative psychosocial factors. We hypothesized that high psychological well being and quality relationships would be associated with vigorous cytokine responses to vaccination. Lymphocytes from 18 individuals were studied for their ability to produce interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) with influenza or hepatitis A immunization. Psychological well being and relationship quality were measured using standardized scales. Significant positive correlations were made between psychological well being and quality relationships and IFN-gamma and IL-10 production to influenza and hepatitis A on day 28 (Pearson correlations: 0.6-0.7; P<0.05). This preliminary study represents one of the first to show positive physiological health is associated with positive psychosocial factors.