[Show abstract][Hide abstract] ABSTRACT: The immunological response during the first 24 hours after traumatic brain injury (TBI) may be a critical therapeutic interval for limiting the secondary neuronal damage that is influenced by enhanced inflammatory mediator expression.
To gain further insight of the early injury response, we examined the expression of several inflammatory genes by real-time qPCR as a function of time or distance from injury in two distinct mammalian models: an ex vivo mouse cortical slice injury system and an in vivo piglet model of brain injury.
Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), chemokine ligands 2 (CCL2), 3 (CCL3), 4 (CCL4), and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNAs increased within 5 h after injury in mouse cortical slices. Chemokine and PTGS2 mRNAs remained elevated in slices at 24 h, whereas IL-1β and TNF-α expressions decreased from earlier peak levels. At 24 h after cortical injury in 1-month-old piglets, the expression of CCL2 mRNA was significantly increased in the lesion core and in the penumbra region. The expression of PTGS2, IL-1β, and TNF-α was variable among the piglets.
These in vitro and large animal models of cortical injury expand our understanding of the early timing and spread of the immunological response and can serve as preclinical systems to facilitate the discovery of therapeutic agents for TBI aimed at regulating inflammatory mediator expression.
Journal of Neuroinflammation 04/2015; 12(1):76. DOI:10.1186/s12974-015-0298-4 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Limiting excessive production of inflammatory mediators is an effective therapeutic strategy for many diseases. It's also a promising remedy for neurodegenerative diseases and central nervous system (CNS) injuries. Glucocorticoids are valuable anti-inflammatory agents, but their use is constrained by adverse side-effects. Activators of NF-E2-related factor-2 (Nrf2) signaling represent an attractive anti-inflammatory alternative. In this study, dexamethasone, a synthetic glucocorticoid, and several molecular activators of Nrf2 were evaluated for efficacy in slices of cerebral cortex derived from adult SJL/J mice. Cortical explants increased expression of IL-1β and TNF-α mRNAs in culture within 5 h of sectioning. This expression was inhibited with dexamethasone in the explant medium or injected systemically in mice before sectioning. Semi-synthetic triterpenoid (SST) derivatives, potent activators of the Nrf2 pathway, demonstrated fast-acting anti-inflammatory activity in microglia cultures, but not in the cortical slice system. Quercetin, luteolin, and dimethyl fumarate were also evaluated as molecular activators of Nrf2. While expression of inflammatory mediators in microglia cultures was inhibited, these compounds did not demonstrate anti-inflammatory efficacy in cortical slices. In conclusion, brain slices were amenable to pharmacological modification as demonstrated by anti-inflammatory activity with dexamethasone. The utilization of Nrf2 activators to limit inflammatory mediators within the CNS requires further investigation. Inactivity in CNS tissue, however, suggests their safe use without neurological side-effects in treating non-CNS disorders. Short-term CNS explants may provide a more accurate model of in vivo conditions than microglia cultures since the complex tissue microenvironment is maintained.
[Show abstract][Hide abstract] ABSTRACT: While it is clear that inbred strains of mice have variations in immunological responsiveness, the influence of genetic background following tissue damage in the central nervous system is not fully understood. A cortical explant system was employed as a model for injury to determine whether the immediate transcriptional response to tissue resection revealed differences among three mouse strains.
Immunological mRNAs were measured in cerebral cortex from SJL/J, C57BL/6J, and BALB/cJ mice using real time RT-PCR. Freshly isolated cortical tissue and cortical sections incubated in explant medium were examined. Levels of mRNA, normalized to β-actin, were compared using one way analysis of variance with pooled samples from each mouse strain.
In freshly isolated cerebral cortex, transcript levels of many pro-inflammatory mediators were not significantly different among the strains or too low for comparison. Constitutive, baseline amounts of CD74 and antisecretory factor (ASF) mRNAs, however, were higher in SJL/J and C57BL/6J, respectively. When sections of cortical tissue were incubated in explant medium, increased message for a number of pro-inflammatory cytokines and chemokines occurred within five hours. Message for chemokines, IL-1α, and COX-2 transcripts were higher in C57BL/6J cortical explants relative to SJL/J and BALB/cJ. IL-1β, IL-12/23 p40, and TNF-α were lower in BALB/cJ explants relative to SJL/J and C57BL/6J. Similar to observations in freshly isolated cortex, CD74 mRNA remained higher in SJL/J explants. The ASF mRNA in SJL/J explants, however, was now lower than levels in both C57BL/6J and BALB/cJ explants.
The short-term cortical explant model employed in this study provides a basic approach to evaluate an early transcriptional response to neurological damage, and can identify expression differences in genes that are influenced by genetic background.
Journal of Neuroinflammation 09/2011; 8:122. DOI:10.1186/1742-2094-8-122 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: GBM (glioblastoma multiforme) is a highly aggressive brain tumour with very poor prognosis despite multi-modalities of treatment. Furthermore, recent failure of targeted therapy for these tumours highlights the need of appropriate rodent models for preclinical studies. In this review, we highlight the most commonly used rodent models (U251, U86, GL261, C6, 9L and CNS-1) with a focus on the pathological and genetic similarities to the human disease. We end with a comprehensive review of the CNS-1 rodent model.
[Show abstract][Hide abstract] ABSTRACT: 2-Cyano-3,12-dioxoolean-1, 9-dien-28-oic acid (CDDO) is a semisynthetic triterpenoid. CDDO derivatives with an amide, butyl ester (BE), imidazolide (IM), or trifluoroethyl amide (TFEA) group at position C-28 of CDDO were evaluated in glial and neuronal cells, in vitro. Changes in intracellular NADPH:quinone oxidoreductase (NQO1) levels, protection against oxidative toxicity, endotoxin-induced free-radical production, and the median lethal concentration (LC50) were assessed. All four CDDO derivatives at nanomolar concentrations increased NQO1 levels in astrocytes and moderately in neurons, but not in microglial cells. Pretreatment with 100 nM of CDDO-amide, CDDO-TFEA, or CDDO-IM protected astrocytes from hydrogen peroxide toxicity. Only CDDO-amide protected neuronal cells. Pretreatment of microglial cells with CDDO derivatives at nanomolar concentrations attenuated endotoxin-induced nitric oxide protection. The effectiveness for NQO1 induction, protection against oxidative toxicity, and attenuation of nitric oxide production, as well as cell viability at higher concentrations, varied among the derivatives with different functional groups at C-28. CDDO-amide had comparable or even a greater effectiveness at altering cytoprotective and immunomodulatory properties while having higher LC50 values for each neural cell type examined. These results indicate that derivatives of CDDO modulate important pathways relevant to many neurological diseases that involve both chronic inflammation and free-radical damage with variable effects based on the functional group at C-28 and cell type.
[Show abstract][Hide abstract] ABSTRACT: Decreased immune surveillance is thought to be one of the mechanisms by which neoplastic cells are able to thrive. When cancer
is located in the nervous system, an immune privileged site, its ability to evade detection, and targeting by immune cells
may contribute to its aggressive behavior. Furthermore, high-grade gliomas, the most frequent and lethal primary brain tumors,
induce both a local and systemic state of immune suppression that hampers efforts to manipulate the immune system as an effective
therapeutic modality. On the other hand, there are rare instances when the immune response elucidated against systemic cancer
causes nervous system injury without direct spread of the tumor. Although the neural injury is thought to be mediated by an
autoimmune process, in most cases it is uncertain if it is caused by a humoral response, a cellular response, or a combination
of both. This chapter reviews concepts related to the unique relationship between the nervous and immune systems, when cancer
is present, as well as immune therapeutic modalities employed when the neural structures are affected directly by a primary
tumor or indirectly in the case of paraneoplastic neurologic syndromes. The distinct immunologic characteristics of the central
nervous system (CNS) become more unique and complex in the setting of neoplastic disease. In 2008, approximately 1,437,180
new cancer cases, including 21,810 arising from the nervous system, were diagnosed in the USA . Gliomas, the most frequent
type of brain tumors, are characterized by the infiltration of normal cerebral tissue, but this rarely results in systemic
metastases. The tumor microenvironment shows a meager inflammatory response often accompanied by systemic immune suppression.
These alterations might be considered epiphenomena unrelated to tumor pathogenesis, but experimental and clinical observations
suggest that the immune system plays an important role in glioma biology. Our current concept of glioma immunobiology lends
strong support to the idea of manipulating the immune system as a therapeutic approach for primary brain tumors. Glioma immunotherapy
has evolved over the years, unfortunately as yet, without a major success. Nevertheless, extraneural or systemic neoplasms
can trigger an immune response that in rare instances have repercussions in the nervous system. These interactions indirectly
cause clinical syndromes that are aptly termed paraneoplastic neurologic syndromes. In some cases, antibodies have been identified
as the element responsible for the phenomenon, but as primary tumors of the brain and spinal cord, the role that the immune
system plays in the pathogenesis of these syndromes has not been clearly elucidated.
KeywordsGliomas-Immunology-Nervous system-Paraneoplastic syndromes
[Show abstract][Hide abstract] ABSTRACT: Theiler's murine encephalomyelitis virus-induced demyelination (TMEVD) and experimental allergic encephalomyelitis (EAE) are the principal animal models of multiple sclerosis (MS). Previously, we provided evidence that Tmevd2 and Eae3 may represent either a shared susceptibility locus or members of a gene complex controlling susceptibility to central nervous system inflammatory demyelinating disease. To explore the genetic relationship between Tmevd2 and Eae3, we generated a D2.C-Tmevd2 interval-specific congenic (ISC) line and three overlapping interval-specific recombinant congenic (ISRC) lines in which the Tmevd2-resistant allele from BALB/cByJ was introgressed onto the TMEVD-susceptible DBA/2J background. These mice, all H2(d), were studied for susceptibility to EAE elicited by immunization with proteolipid protein peptide 180-199. Compared with DBA/2J mice, D2.C-Tmevd2 mice developed a significantly less severe clinical disease course and EAE pathology in the spinal cord, confirming the existence of Eae3 and its linkage to Tmevd2 in this strain combination. Compared with DBA/2J and D2.C-Tmevd2, all three ISRC lines exhibited clinical disease courses of intermediate severity. Neither differences in ex vivo antigen-specific cytokine nor proliferative responses uniquely cosegregated with differences in disease severity. These results indicate that multiple quantitative trait loci (QTLs) within the Tmevd2/Eae3 interval influence EAE severity, one of which includes a homology region for a QTL found in MS by admixture mapping.
Genes and immunity 12/2010; 11(8):649-59. DOI:10.1038/gene.2010.40 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-beta, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.
Proceedings of the National Academy of Sciences 02/2010; 107(7):3081-6. DOI:10.1073/pnas.0913828107 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS.
Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were pre-clinical, at clinical onset, and near disease end-stage. Changes in CD11b expression were compared to the detection of MHC class II and CD68 microglial activation markers in the ventral horn of the spinal cord, as well as to the changes in astrocytic GFAP expression.
Our study reveals an accumulation of microglia/macrophages both in the spinal cord and peripheral nerve prior to clinical onset based on CD11b tissue expression. The microglia formed focal aggregates in the ventral horn and became more widespread as the disease progressed. Hypertrophic astrocytes were not prominent in the ventral horn until after clinical onset, and the enhancement of GFAP did not have a strong correlation to increased CD11b expression. Detection of MHC class II and CD68 expression was found in the ventral horn only after clinical onset. The macrophages in the ventral nerve root and sciatic nerve of hmSOD1 rats were observed encircling axons.
These findings describe for the first time in the hmSOD1 rat transgenic model of ALS that enhancement of microglia/macrophage activity occurs pre-clinically both in the peripheral nerve and in the spinal cord. CD11b expression is shown to be a superior indicator for early immunological changes compared to other microglia activation markers and astrogliosis. Furthermore, we suggest that the early activity of microglia/macrophages is involved in the early phase of motor neuron degeneration and propose that studies involving immunomodulation in hmSOD1transgenic models need to consider effects on macrophages in peripheral nerves as well as to microglia in the spinal cord.
Journal of Neuroinflammation 01/2010; 7:8. DOI:10.1186/1742-2094-7-8 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genes controlling immunopathologic diseases of differing etiopathology may also influence susceptibility to autoimmune disease. B10.D1-H2(q)/SgJ mice with a 2538 G-->A missense mutation in the tyrosine kinase-2 gene (Tyk2) are susceptible to Toxoplasma gondii yet resistant to autoimmune arthritis, unlike the wild-type B10.Q/Ai substrain. To understand whether Tyk2 is also important in a second autoimmune model, experimental allergic encephalomyelitis (EAE) was induced in B10.D1-H2(q)/SgJ (Tyk2(A)) and B10.Q/Ai (Tyk2(G)) mice with the myelin oligodendrocyte glycoprotein peptide 79-96. B10.D1-H2(q)/SgJ mice were resistant to EAE whereas B10.Q/Ai mice were susceptible, and a single copy of the Tyk2(G) allele conferred EAE susceptibility in F(1) hybrids. Furthermore, EAE resistance in B10.D1-H2(q)/SgJ mice was overridden when pertussis toxin (PTX) was used to mimic the effects of environmental factors derived from infectious agents. Numerous cytokines and chemokines were increased when PTX was included in the immunization protocol. However, only RANTES, IL-6, and IFN-gamma increased significantly with both genetic compensation and PTX treatment. These data indicate that Tyk2 is a shared autoimmune disease susceptibility gene whose genetic contribution to disease susceptibility can be modified by environmental factors. Single nucleotide polymorphisms like the one that distinguishes Tyk2 alleles are of considerable significance given the potential role of gene-by-environment interactions in autoimmune disease susceptibility.
The Journal of Immunology 06/2009; 182(12):7776-83. DOI:10.4049/jimmunol.0900142 · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.
To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5-12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or alphaPD1 ligand were studied.
Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation.
In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.
Journal of Neuroinflammation 11/2008; 5:48. DOI:10.1186/1742-2094-5-48 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Niemann-Pick C disease (NPC) is a fatal, neurovisceral genetic disorder. Cell culture studies showed that NPC1 or NPC2 mutations cause malfunctions in cellular cholesterol trafficking and lead to accumulation of cholesterol and other lipids in the late endo/lysosomes. Previous work showed that neuronal cholesterol accumulation occurs in the brains of young postnatal NPC1-/- mice. Here, to evaluate the potential of partial blockage of cholesterol biosynthesis as a therapy for the NPC disease, we first developed a simple method to monitor the relative rates of lipid biosynthesis in mice brains. We next administered squalene synthase inhibitor (SSI) CP-340868 to young mice. The results show that treating 8-day-old NPC1-/- mice with CP-340868 for 6 days significantly inhibits cholesterol biosynthesis in the mice brains. It reduces neuronal cholesterol accumulation, reduces GM3 ganglioside accumulation, and diminishes astrogliosis in the brain. These results suggest that neuronal cholesterol accumulation contributes to early pathogenesis in the NPC1-/- mice brains. The SSI treatment also reduced brain galactolipid content, suggesting that blocking endogenous cholesterol synthesis in the young mice brains may disrupt the normal myelin maturation processes. The methods described in the current work have general applicability for lipid metabolism studies in mice brains in various pathophysiological conditions.
[Show abstract][Hide abstract] ABSTRACT: This study examined the effects of a standard breast cancer chemotherapeutic protocol on learning and memory in rats. Ovariectomized rats were treated once a week for 3 weeks with a combination of cyclophosphamide and doxorubicin prior to training in a classical fear conditioning task. Training took place 1 week after the final treatment. During the training session, an auditory stimulus (a tone) was paired with a mild foot-shock. The resulting conditioned fear to the tone (cue-specific fear) and to the training environment (contextual fear) was measured in subsequent test sessions. Chemotherapy did not affect the acquisition of the conditioned response (freezing) during the training session or the expression of fear during the tone test session. In contrast, rats treated with cyclophosphamide and doxorubicin exhibited decreased freezing during the context test session, suggestive of a specific deficit in hippocampal-related learning and memory. Together, these data indicate that administration of cyclophosphamide and doxorubicin may have toxic effects on the hippocampus and results in specific learning deficits shortly after treatment has ended.
Behavioural Brain Research 08/2007; 181(1):168-72. DOI:10.1016/j.bbr.2007.04.003 · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Macrophages are intimately involved in the pathogenesis of inflammatory neuropathies. The contribution of resident endoneurial macrophages is unknown since their differentiation from infiltrating macrophages is difficult due to missing cellular markers. Previous studies demonstrated the participation of resident macrophages in Wallerian degeneration and the pathogenesis of hereditary neuropathies. The question arises whether resident macrophages are involved in experimental autoimmune neuritis (EAN) where they could contribute to immunosurveillance and antigen presentation. To address this question we used bone marrow chimeric rats, allowing the differentiation between resident and hematogenous cells. Immunohistochemistry and in situ hybridization were applied on to identify and characterize resident macrophages in terms of morphological features, expression of activation markers, proliferation, phagocytosis, and MHC-II expression. Endoneurial macrophages of resident origin were detectable at all stages of disease with a contribution of at least 27% of the total macrophages. They appeared activated by morphological and immunohistochemical criteria and proliferated early. MHC-II-positive resident macrophages were observed that had phagocytosed myelin. These results demonstrate that the macrophage response in EAN is partly of intrinsic origin. The rapid activation and proliferation of resident endoneurial macrophages points toward an active role of these cells in inflammatory peripheral nerve disease, especially early in disease.
Journal of Neuropathology and Experimental Neurology 06/2006; 65(5):499-507. DOI:10.1097/01.jnen.0000229239.43866.d1 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many neurological disorders include a neuroinflammatory response in the central nervous system (CNS) that contributes to the pathogenesis and progression of the condition. However, the question of whether neuroinflammation plays a role in alcohol-induced brain damage has received little attention. This symposium at the 2004 World Congress on Biomedical Alcohol Research held in Mannheim, Germany considered for the first time the relationship between alcohol neuropathology and neuroinflammation. The organizers and co-chairs were Peter J. Syapin and Cynthia J. M. Kane. Neuroinflammatory responses including glial activation, demyelination, neuronal damage and neurodegeneration may contribute to the neurological deficits associated with alcoholism, alcohol abuse, fetal alcohol syndrome or alcohol-related neurodevelopmental disorder. A substantial body of literature indicates that alcohol directly affects astroglial cell function, including inflammation-related activity. In addition, emerging data indicate that alcohol affects microglial cell development and function in specific ways that interfere with microglial interactions with the immune system and with neurons. This symposium provided alcohol researchers with background information on CNS immunity and inflammatory processes and examined emerging experimental evidence that neuroinflammatory processes might be involved in alcohol-induced brain damage. A brief introduction was followed by four presentations, the first two describing the nature of immune reactions in the CNS and the role of astrocytes and microglia in neuroinflammatory processes. The presentations included: (1) Initiation of inflammation in the nervous system, by William Hickey; (2) Microglia – Interface between immune system and brain, by Helmut Kettenmann; (3) Ethanol and neuroinflammatory response in brain astroglial, by Peter Syapin; and (4) Microglia are targets of alcohol pathogenesis in the developing CNS, by Cynthia Kane.
Alcoholism Clinical and Experimental Research 05/2006; 29(6):1080 - 1089. DOI:10.1097/01.ALC.0000167961.39176.E6 · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune pancreatitis (AIP), a recently defined disease of unknown etiology, is characterized by inflammatory infiltrates in the pancreas with conspicuous involvement of the ducts. The disease clinically manifests in humans as epigastric pain, weight loss, and jaundice. This report describes the development of a novel animal model of this disease in the rat, which we have termed experimental autoimmune pancreatitis. Adoptive transfer of amylase-specific CD4(+) T cells was able to confer pancreatitis to naive syngeneic recipient animals. No treatments before the adoptive transfer of T cells were necessary for disease to ensue, and the severity of disease was proportional to the number of T cells administered. The pancreatic lesions of rats with experimental autoimmune pancreatitis were characterized histologically as overwhelmingly lymphocytic with occasional plasma cells, neutrophils, and mast cells. Acinar tissue destruction and ductular inflammation were common features, with less frequent involvement of larger ducts. Immunohistochemical analysis revealed the presence of CD4(+) T cells in large numbers as well as CD8(+) T cells, macrophages, and dendritic cells. Expression of MHC I and MHC II also increased at the site of the lesion. Clinically, the disease manifested as either failure to gain weight at a rate concomitant with control animals or as outright weight loss. Thus, administration of activated CD4(+) T cells specific for the pancreatic enzyme amylase can induce pancreatitis in the rat in a manner that is reminiscent of human AIP.
American Journal Of Pathology 04/2005; 166(3):729-36. DOI:10.1016/S0002-9440(10)62294-8 · 4.60 Impact Factor