Of Mice and Not Men: Differences between Mouse and Human Immunology

Mestas, Javier; Hughes, Christopher C.W.

doi:10.4049/jimmunol.172.5.2731

Cited by 2,992 publications

(2,440 citation statements)

References 104 publications

Supporting

Mentioning

2,322

Contrasting

Unclassified

Order By: Relevance

“…As peripheral B cells can be exposed to TLR agonists prior to CD40 stimulation, during infection or vaccination, we determined the effect of pre-treating human and mouse B cells with TLR7/8 agonists, with or without BCR engagement, on subsequent CD154 stimulation. Analysis of both species was done to ensure validity of the mouse as a model species for human B cell responses, as mouse and human B cells can respond differently to particular TLR agonists [30]. The pretreatment of B cells with TLR agonist or TLR + BCR stimuli enhanced the production of CD40-induced IL-6 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

View full text Add to dashboard Cite

During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells. IntroductionNatural immune responses to microbes and responses induced by vaccination involve the cooperation of innate and adaptive immunity. B lymphocytes express receptors that allow them to respond to both antigen-specific and innate immune stimuli [1,2]. One of the key receptors involved in adaptive humoral responses is the TNF receptor superfamily member CD40. The interaction of CD40 on B cells with its ligand CD154, expressed by activated T cells, is integral to immunoglobulin production, isotype switching, and the formation of germinal centers [3], important events in the development of long-lived humoral memory. CD40 stimulation also contributes to B cell antigen presentation by the upregulation of T cell co-stimulatory molecules and production of acute phase cytokines such as . Previous studies have shown that dual stimulation of B cells through the BCR and CD40 leads to an enhancement of Ig and cytokine production [7]. However, the effects and mechanisms of interactions between innate immune receptors and BCR or CD40 expressed by B cells are not yet well defined.B cells can be activated through engagement of a variety of innate immune receptors, including Toll-like receptors (TLR). TLR are related to the Drosophila receptor Toll, important for dorsal-ventral patterning in the developing fly as well as resistance to microbes [8]. The TLR in higher organisms act as sensors of infection or 'danger' by recognizing molecular patterns associated with microbes and/or cellular damage. As natural surveyors of environmental stresses, TLR induce immune cell activity and direct the initial stages of immune responses [9]. Of the 13 TLR mammalian genes [11,12]. TLR7 and -8 bind singlestranded RNA as natural ligands, but also confer responsiveness to guanosine derivatives and the imi...

show abstract

Section: Resultsmentioning

confidence: 99%

“…Notably, the effects of dual stimulation were observed in both human and mouse B cells. Species differences between human and mouse TLR expression and response to TLR agonists have been described [30]. Human TLR8 recognizes R848, while mouse TLR8 is reported to be nonresponsive to this compound [13].…”

Section: Discussionmentioning

confidence: 99%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…Although useful information has been and will continue to be gleaned from traditional studies of airway and other transplantations among allogeneic mouse strains, [3][4][5][6][7] there are a considerable number of differences between mouse and human immune systems. 8,9 As one of many examples, oligoclonal daughter progeny of human T cells that have undergone repetitive, antigen-driven proliferations develop markedly dysregulated and pathogenic characteristics and functions, including increased expression of NK-cell receptors, absence of cell-surface CD28, discordant expression of many activation and maturation markers, telomere shortening, and diminished production of FoxP3. 13,14,[17][18][19][20] Unlike normal human lymphocytes, these CD4 T-cell progeny of repetitive prior cell divisions also produce cytolytic mediators, have enhanced facultative and constitutive production of diverse proinflammatory and profibrotic cytokines, and are resistant to antiproliferative effects of calcineurin inhibitors 14 and glucocorticoids (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…9,17 Multiple other species-specific differences in structure and functions of adaptive immune mechanisms have been described. 8,9 Unlike the T cells of mice, activated human T lymphocytes express MHC class II, which may in turn may play a role (or multiple roles) in amplification of immune responses and/or in homeostatic regulation of these processes. 25,26 Calcium influxes during activation of human T cells can occur through Kv1.3 K ϩ channels, currently under study as a potential target for therapeutic modulation, 27 whereas murine T cells do not express this ion-flux apparatus.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Not surprisingly, some immunological therapies that appeared promising in murine subjects have not translated into comparably effective human treatments. 10,11 The availability of a facile model of human immune effector cell and target organ interactions that mimics the phenotype of clinical disease in situ could be very useful for fundamental studies, and a unique, potentially more valid tool for early trials of immunosuppressive agents and biological response modifiers.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

Xue

Zhu

George

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways. Chronic lung allograft rejection typically manifests with obliterative bronchiolitis (OB), a small airway fibroproliferative disease process characterized by varying degrees of airway luminal obliteration with fibrinous granulation tissue. 1 Lung transplant recipients with OB develop expiratory airflow obstruction, which is often inexorably progressive, and have increased predilection for infection. 2 Despite extensive investigation, as well as incremental advances in donor organ preservation, surgical techniques, immunosuppressive regimens, and infection prophylaxis, OB remains the single most frequent cause of late graft dysfunction and death after lung transplantation. 2 Current limitations in prevention and treatment of OB likely reflect incomplete understanding of the responsible immunopathogenic mechanisms. Accordingly, having a model to generate novel insights regarding the disease paradigm, and a ready means to test these hypotheses, could be a boon for the development of more effective modalities to prevent or counter this frequent complication of lung transplantation.Animal models have been immeasurably important in advancing our understanding of many disease processes, including allograft rejection mechanisms. 3 With particular respect to pulmonary transplantation, heterotopic tracheal allografts in mice undergo histological abnormalities that reproduce the progression of OB in humans, including an initial lymphocytic infiltration, followed by successive stages of epithelial metaplasia and denudation and, ultimately, intraluminal fibroproliferation. [3][4][5][6][7] Although this mo...

show abstract