Many studies of Mycobacterium tuberculosis infection and immunity have used mouse models. However, outcomes of vaccination and challenge with M. tuberculosis in inbred mouse strains do not reflect the full range of outcomes seen in people. Previous studies indicated that the novel Diversity Outbred (DO) mouse population exhibited a spectrum of outcomes after primary aerosol infection with M. tuberculosis. Here, we demonstrate the value of this novel mouse population for studies of vaccination against M. tuberculosis aerosol challenge. Using the only currently licensed tuberculosis vaccine, we found that the DO population readily controlled systemic Mycobacterium bovis BCG bacterial burdens and that BCG vaccination significantly improved survival across the DO population upon challenge with M. tuberculosis. Many individual DO mice that were vaccinated with BCG and then challenged with M. tuberculosis exhibited low bacterial burdens, low or even no systemic dissemination, little weight loss, and only minor lung pathology. In contrast, some BCG-vaccinated DO mice progressed quickly to fulminant disease upon M. tuberculosis challenge. Across the population, most of these disease parameters were at most modestly correlated with each other and were often discordant. This result suggests the need for a multiparameter metric to better characterize “disease” and “protection,” with closer similarity to the complex case definitions used in people. Taken together, these results demonstrate that DO mice provide a novel small-animal model of vaccination against tuberculosis that better reflects the wide spectrum of outcomes seen in people.
IMPORTANCE We vaccinated the Diversity Outbred (DO) population of mice with BCG, the only vaccine currently used to protect against tuberculosis, and then challenged them with M. tuberculosis by aerosol. We found that the BCG-vaccinated DO mouse population exhibited a wide range of outcomes, in which outcomes in individual mice ranged from minimal respiratory or systemic disease to fulminant disease and death. The breadth of these outcomes appears similar to the range seen in people, indicating that DO mice may serve as an improved small-animal model to study tuberculosis infection and immunity. Moreover, sophisticated tools are available for the use of these mice to map genes contributing to control of vaccination. Thus, the present studies provided an important new tool in the fight against tuberculosis.
Antibodies (Abs) to donor HLA (donor‐specific antibodies [DSA]) have been associated with transplant glomerulopathy (TG) following kidney transplantation (KTx). Immune responses to tissue‐restricted self‐antigens (self‐Ags) have been proposed to play a role in chronic rejection. We determined whether KTx with TG have immune responses to self‐Ags, Collagen‐IV (Col‐IV) and fibronectin (FN). DSA were determined by solid phase assay, Abs against Col‐IV and FN by enzyme‐linked immunosorbent assay and CD4+ T cells secreting interferon gamma (IFN‐γ), IL‐17 or IL‐10 by ELISPOT. Development of Abs to self‐Ags following KTx increased the risk for TG with an odds ratio of 22 (p‐value = 0.001). Abs to self‐Ags were IgG and IgM isotypes. Pretransplant Abs to self‐Ags increased the risk of TG (22% vs. 10%, p < 0.05). Abs to self‐Ags were identified frequently in KTx with DSA. TG patients demonstrated increased Col‐IV and FN specific CD4+ T cells secreting IFN‐γ and IL‐17 with reduction in IL‐10. We conclude that development of Abs to self‐Ags is a risk factor and having both DSA and Abs to self‐Ags increases the risk for TG. The increased frequency of self‐Ag‐specific IFN‐γ and IL‐17 cells with reduction in IL‐10 demonstrate tolerance breakdown to self‐Ags which we propose play a role in the pathogenesis of TG.
Plasma cells (PCs) are the major source of pathogenic allo-and autoantibodies and have historically demonstrated resistance to therapeutic targeting. However, significant recent clinical progress has been made with the use of second-generation proteasome inhibitors (PIs). PIs provide efficient elimination of plasmablast-mediated humoral responses; however, long-lived bone marrow (BM) resident PCs (LLPCs) demonstrate therapeutic resistance, particularly to first-generation PIs. In addition, durability of antibody (Ab) reduction still requires improvement. More recent clinical trials have focused on conditions mediated by LLPCs and have included mechanistic studies of LLPCs from PI-treated patients. A recent clinical trial of carfilzomib (a second-generation irreversible PI) demonstrated improved efficacy in eliminating BM PCs and reducing anti-HLA Abs in chronically HLA-sensitized patients; however, Ab rebound was observed over several weeks to months following PI therapy. Importantly, recent murine studies have provided substantial insights into PC biology, thereby further enhancing our understanding of PC populations. It is now clear that BMPC populations, where LLPCs are thought to primarily reside, are heterogeneous and have distinct gene expression, metabolic, and survival signatures that enable identification and characterization of PC subsets. This review highlights recent advances in PC biology and clinical trials in transplant populations.
Production of IFN-γ is a key innate immune mechanism that limits replication of intracellular bacteria such as Francisella tularensis (Ft) until adaptive immune responses develop. Previously, we demonstrated that the host cell types responsible for IFN-γ production in response to murine Francisella infection include not only natural killer (NK) and T cells, but also a variety of myeloid cells. However, production of IFN-γ by mouse dendritic cells (DC) is controversial. Here, we directly demonstrated substantial production of IFN-γ by DC, as well as hybrid NK-DC, from LVS-infected wild type C57BL/6 or Rag1 knockout mice. We demonstrated that the numbers of conventional DC producing IFN-γ increased progressively over the course of 8 days of LVS infection. In contrast, the numbers of conventional NK cells producing IFN-γ, which represented about 40% of non-B/T IFN-γ-producing cells, peaked at day 4 after LVS infection and declined thereafter. This pattern was similar to that of hybrid NK-DC. To further confirm IFN-γ production by infected cells, DC and neutrophils were sorted from naïve and LVS-infected mice and analyzed for gene expression. Quantification of LVS by PCR revealed the presence of Ft DNA not only in macrophages, but also in highly purified, IFN-γ producing DC and neutrophils. Finally, production of IFN-γ by infected DC was confirmed by immunohistochemistry and confocal microscopy. Notably, IFN-γ production patterns similar to those in wild type mice were observed in cells derived from LVSinfected TLR2, TLR4, and TLR2xTLR9 knockout (KO) mice, but not from MyD88 KO mice. Taken together, these studies demonstrate the pivotal roles of DC and MyD88 in IFN-γ production and in initiating innate immune responses to this intracellular bacterium.
Solid organ transplantation is a life‐saving procedure for patients with end‐stage organ disease. Over the past 70 years, tremendous progress has been made in solid organ transplantation, particularly in T‐cell‐targeted immunosuppression and organ allocation systems. However, humoral alloimmune responses remain a major challenge to progress. Patients with preexisting antibodies to human leukocyte antigen (HLA) are at significant disadvantages in regard to receiving a well‐matched organ, moreover, those who develop anti‐HLA antibodies after transplantation face a significant foreshortening of renal allograft survival. Historical therapies to desensitize patients prior to transplantation or to treat posttransplant AMR have had limited effectiveness, likely because they do not significantly reduce antibody levels, as plasma cells, the source of antibody production, remain largely unaffected. Herein, we will discuss the significance of plasma cells in transplantation, aspects of their biology as potential therapeutic targets, clinical challenges in developing strategies to target plasma cells in transplantation, and lastly, novel approaches that have potential to advance the field.
Introduction: We report one of few documented cases of a severe anaphylactic reaction with angioedema to polyethylene glycol (PEG).
Case Report: The patient presented 30 minutes after onset of his symptoms and quickly developed hypoxia and hypotension refractory to intramuscular epinephrine, intravenous fluids, methylprednisolone, and supplemental oxygen via non-rebreather mask. He ultimately required intubation, an epinephrine infusion, and admission to the medical intensive care unit.
Discussion: This case depicts a clinical reaction to PEG, a medication rarely implicated in severe anaphylaxis or angioedema.
Conclusion: The allergenic potential of PEG-containing products should be raised, and providers should have a heightened awareness of these potential side effects.
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