A Distinct Th1 Immune Response Precedes the Described Th2 Response in Islet Xenograft Rejection

Krook, Henrik; Hagberg, Anette; Song, Z.; Landegren, Ulf; Wennberg, Lars; Korsgren, Olle

doi:10.2337/diabetes.51.1.79

Cited by 44 publications

(40 citation statements)

References 33 publications

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“…The cellular infiltration of ICC xenograft rejection in rodents resembles that of a DTH reaction, the prototype of a Th1 response. Previous findings in this laboratory using real-time quantitative RT-PCR to characterize cytokine kinetics during ICC xenograft rejection in rats have implicated a major role of Th1 cells in the initial stages of ICC xenograft rejection followed by Th2-associated responses in the later phases (16). Notably, in this model, the transferred T-cells were harvested from the donor animals on day 6 after ICC transplantation, and xenograft rejection in the athymic (nu/nu) mice was completed after an additional 4 -6 days.…”

Section: Discussionmentioning

confidence: 99%

“…ICC was prepared from porcine fetuses (gestational age 70 Ϯ 5 days) as previously described (16). The ICC were cultured for 4 days in RPMI-1640 (Sigma Chemicals, St. Louis, MO) supplemented with 10 mmol/l nicotinamide (Sigma Chemicals).…”

Section: Methodsmentioning

confidence: 99%

“…mRNA from the grafts was extracted, immobilized onto oligo(dT)-coated manifold supports (20), and reverse-transcribed to cDNA according to a previously described protocol (16). 5Ј nuclease assays for quantitative analysis of the obtained cDNA were performed in triplicate using the iCycler iQ RealTime PCR Detection System (Bio-Rad Laboratories, Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

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A New Murine Model of Islet Xenograft Rejection

et al. 2003

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A new murine model of porcine islet-like cell cluster (ICC) xenograft rejection, avoiding interference of unspecific inflammation, was introduced and used to investigate rejection mechanisms. Athymic (nu/nu) mice were transplanted with syngeneic, allogeneic, or xenogeneic islets under the kidney capsule. After the original transplantation, immune cells in porcine ICC xenografts undergoing rejection in native immunocompetent mice were transferred to the peritoneal cavity of the athymic mice. At defined time points after transfer, the primary grafts were evaluated by immunohistochemistry and real-time quantitative RT-PCR to estimate cytokine and chemokine mRNA expression. Transfer of immunocompetent cells enabled athymic (nu/nu) mice to reject a previously tolerated ICC xenograft only when donor and recipient were matched for major histocompatibility complex (MHC). In contrast, allogeneic and syngeneic islets were not rejected. The ICC xenograft rejection was mediated by transferred T-cells. The main effector cells, macrophages, were shown to be part of a specific immune response. By day 4 after transplantation, there was an upreglation of both Th1-and Th2-associated cytokine transcripts. The transferred T-cells were xenospecific and required MHC compatibility to induce rejection. Interaction between the TCR of transferred T-cells and MHC on host endothelial cells and/or macrophages seems necessary for inducing ICC xenograft rejection.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A New Murine Model of Islet Xenograft Rejection

et al. 2003

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“…More specifi cally, analysis of mRNA expression of cytokines at graft sites via RT-PCR revealed an initial Th1 response, characterized by activated macrophage intrusion into the graft site and aggregation of T-cells peripheral to the foreign tissue. The Th1 mechanism, responsible for a majority of the graft destruction, was then followed by a Th2 response resulting in elevated anti-FP ICC IgG levels along with eosinophil infi ltration [ 64 ].…”

Section: Fetal Porcine Islet-like Cell Clustersmentioning

confidence: 99%

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Krishnan

Foster

et al. 2016

Methods in Molecular Biology

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Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of signifi cant parameters of bioencapsulation device design and manufacture (i.e., purifi cation protocols, surface-modifi cation grafting techniques, alginate composition modifi cations) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specifi c pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defi ning characteristics of the response itself.

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“…Reverse transcription was carried out using the oligoT primer and AMV reverse transcriptase (ABgene, Epsom, UK). Primers and probes for the 5´ nuclease assay were adopted from Krook et al (2002). The expression of IFN-γ and IL-4 was measured in duplex reactions with β-actin as a reference gene.…”

Section: Cytokine Gene Expressionmentioning

confidence: 99%

Effects of postnatal exposure to benzo[a]pyrene on the immunity of immature rats

Matiašovic¹,

Levá²,

Mašková³

et al. 2008

Vet. Med. - Czech

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ABSTRACT:To determine the effect of benzo [a]pyrene (B[a]P) on the developing immune system of immature rats, newborn animals received different concentrations (0.1, 1.0 and 10.0 mg/kg/day) of B[a]P in the first 14 days after birth. These rats were euthanised on day 23 of the experiment and it was found that the decreasing numbers of erythrocytes were in direct correlation to the dose of B[a]P. In subject animals, the overall counts of T cells in the spleen and the mitogenic activity increased. A decrease in the production of both IFN-γ and IL-4 (measured at the mRNA level) as well as the decreasing IFN-γ/IL-4 ratio in rat splenocytes were dependent on the dose of B[a]P. From this we may deduce that exposure to B[a]P in immature animals may modulate the immune response to infection and/or vaccination. Keywords: polycyclic aromatic hydrocarbons; immunity; IFN-γ; IL-4; cytokinesPolycyclic aromatic hydrocarbons (PAHs) are mostly anthropogenic in origin and are released both as a result of incomplete combustion in coal, oil, gasoline and wood and in consequence of some other pyrolytic processes (Motelay-Massei et al., 2007). Benzo [a]pyrene (B[a]P) is widely used as a prototypical PAH which exhibits significant genotoxicity and negative effects on different components of the immune system. The impact of B[a]P on the immune system varies from reduced humoral immunity to increased T cell mitogenic activity (Davila et al., 1996;Burchiel and Luster, 2001;Burchiel et al., 2004 (Harper et al., 1996).In earlier studies, it was the toxic effects of B[a]P that were mainly described and decreases in humoral and cell-mediated immunity were documented (Ward et al., 1984;Dean et al., 1986). The differences in the sensitivity of humans and rodents to varying doses of B[a]P were also described and the observation that humans were 10-100 times more sensitive to toxic effects of B[a]P than rodents was made (Davila et al., 1996). Depending on their doses, different fractions of the reconstituted PAH mixture show different effect on the humoral and cell-mediated immunity in mouse splenocytes (Harper et al., 1996). Interestingly, in more recent studies, signs of a possible adjuvant effect of PAHs or DE were shown. For example, increasing in vitro mitogenic activity of mouse spleen T cells in the presence of 1 µM B[a]P was documented (Burchiel et al., 2004). Also Fujimaki et al. (2001) found an increasing production of IFN-γ but not IL-4 and IL-5 by splenocytes in mice exposed to DE. In contrast, the work of Diaz-Sanchez et al. (1997) showed a decreased expression of mRNA for Th1-type cytokines (IFN-γ and IL-2) but an elevated expression for other cytokines (IL-4, 5, 6, 10, and 13) in human cells isolated from nasal lavages after stimulation by ragweed allergens and exposure to DE particles. The mechanism of this effect is not clear, but seems to be complex due to possible interaction between PAH metabolites and different lymphocyte signalling pathways such as the aryl hydrocarbon

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A Distinct Th1 Immune Response Precedes the Described Th2 Response in Islet Xenograft Rejection

Cited by 44 publications

References 33 publications

A New Murine Model of Islet Xenograft Rejection

A New Murine Model of Islet Xenograft Rejection

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Effects of postnatal exposure to benzo[a]pyrene on the immunity of immature rats

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