CD4+ cytolytic effectors are inefficient in the clearance of Listeria monocytogenes

Cytotoxic T lymphocytes (CTL) recognize and lyse target cells through the interaction of the T-cell receptor complex with the class I or class II major histocompatibility complex (MHC). The production of class I-restricted CTL has been shown to be critical to the elimination of specific pathogens including . However, the function of class II-restricted CTL in the clearance of intracellular pathogens is poorly understood. H-2β-microglobulin-deficient mice (βM−/−) are not able to produce CD8 CTL in response to infection with . We used this model to evaluate the efficacy of class II-restricted CTL, in the absence of a class I-restricted response, during a primary infection with . We demonstrate that, despite their effectiveness in adoptive transfer of protection, -specific CD4 class II-restricted cytotoxic lymphocytes are ineffective in decreasing titres of in the spleen after an established infection. In βM−/− mice, persistence of in the spleen was found preferentially in class II-negative cells. Surprisingly, class I-restricted CTL from C57BL/6 mice were capable of decreasing bacterial titres during an established infection even in the absence of detectable class I on the surface of cells from βM−/− mice. These data strongly suggest that, in the absence of a class I-restricted response, pathogens that elicit a class II-restricted cytotoxic response may escape prompt eradication by the immune system

Development and validation of the Patient‐Physician Relationship Scale among patients with irritable bowel syndrome

BackgroundAn effective patient‐physician relationship (PPR) is essential to the care of patients with irritable bowel syndrome (IBS). We sought to develop and validate an IBS‐specific instrument to measure expectations of the PPR.MethodsWe conducted structured focus groups about PPRs with 12 patients with IBS. Qualitative analysis was used to generate a questionnaire (the Patient‐Physician Relationship Scale [PPRS]), which was modified with input from content experts and usability testing. For validation, we administered it online to US adults with IBS. Participants also completed the Functional Bowel Disorder Severity Index, the Rome III Adult Functional gastrointestinal (GI) Disorder Criteria Questionnaire, and modified versions of the Communication Assessment Tool (CAT‐15) and Patient‐Doctor Relationship Questionnaire (PDRQ‐9). We performed principal components factor analysis for the PPRS.Key ResultsThe PPRS contained 32 questions with responses on a 7‐item Likert scale. Themes included interpersonal features, clinical care expectations, and aspects of communication. One thousand and fifty‐four eligible individuals completed the survey (88% completion rate). Most participants were middle aged (mean 48 years, SD 16.3), white (90%), and female (86%). Factor analysis showed only one relevant factor, relating to quality of PPR. The final scale ranged from possible‐96 to +96 (mean 62.0, SD 37.6). It correlated moderately with the CAT‐15 (r=.40, P<.001) and PDRQ‐9 (r=.30, P<.001), establishing concurrent validity.Conclusions & InferencesWe describe the development and validation of the first questionnaire for use in measuring patient expectations of the PPR, which can be used for future outcomes studies and training physicians.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138227/1/nmo13106.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138227/2/nmo13106_am.pd

A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies