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Rutemark, Christian, et al.
(författare)
B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
The complement system, including the complement receptors 1 and 2 (CR1/2), is crucial for the development of antibody responses against a wide range of antigens. Cr2-/- mice are deficient in both CR1 and CR2 and respond poorly upon immunization with antigen alone and with IgM-containing immune complexes. In mice, CR1/2 are expressed exclusively on B cells and follicular dendritic cells (FDC) but it is not clear which of the two cell-types that need to express the receptors for a normal antibody response. Here, bone marrow chimeras were used to distinguish between B cells and FDC. The animals were immunized with SRBC alone or with IgM anti-SRBC and SRBC. For an antibody response to SRBC alone, CR1/2 expression on FDC was crucial. When CR1/2+ FDC were present, B cells from Cr2-/- mice produced equal amounts of antibodies against SRBC as did B cells from WT. However, the response to IgM-SRBC complexes was more efficient in the presence of CR1/2+ B cells although CR1/2+ FDC still played a dominant role. In conclusion, antibody responses to antigen alone required CR1/2+ FDC, whereas CR1/2 expression on B cells was irrelevant. In contrast, in antibody responses to IgM-IC, presence of CR1/2+ B cells led to a higher and more rapid onset of the antibody response.
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Mullazehi, Mohammed, 1966-, et al.
(författare)
Anti-type II collagen-IC-induced production of IL-1β and TNF-α, stimulate production of matrix met-alloproteinases from monocytes/rheumatoid arthritis synovial fibroblast co-cultures
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
Objective: To establish an in vitro model that might explain the association between early joint destruction and the appearance of collagen type II (CII) antibodies in early Rheumatoid Arthritis (RA) patients. This RA pannus tissue model utilizes immune complexes (IC) containing CII-antibodies as stimulus and monocytes and synovial fibroblastsas responder cells. Methods: Peripheral blood mononuclear cells (PBMC) and RA synovial fibroblasts (RASF) were stimulated with IC individually as well in co-cultures. Monocytes were depleted to define the responder cells, and TNF-α and IL-1β were neutralized to study the effect on MMP production. TNF-α, IL-1β, MMP-1, MMP-8 and MMP-13 were measured in cell culture super-natants using ELISA.Results: Anti-CII-containing IC induced production of TNF-α, IL-1β and MMP-1 in PBMC cultures, and TNF-α, IL-1β, MMP-1 and MMP-8 in PBMC/fibroblast co-cultures, in a dose-dependent manner. IC-induced MMP-1 responses were stronger and more associated with induced produc-tion of IL-1β as compared to MMP-8 responses. Baseline production of IL-1β and MMP-1 increased significantly in co-cultures as compared to indi-vidual cultures, whereas this was not the effect for TNF-α and MMP-8. Monocyte depletion decreased TNF-α, IL-1β and MMP-1 production, while the effect on MMP-8 production was variable. Cytokine neutralization re-vealed that IL-1β was a stronger inducer of MMP-1 than was TNF-α.Conclusion:Synergistic actions between RASF and PBMC result in enhanced anti-CII IC-induced production of IL-1β and MMP-1. IL-1β and MMP-1 are regu-lated in parallel as anti-CII IC-induced IL-1β supports the production of MMP-1. MMP-8 seems to be regulated by other means. Anti-CII IC-induced TNF-α seems to be inferior to IL-1β concerning MMP-1 induction. The fact that IC stimulated synovial macrophages and fibroblasts to produce MMP, which are the first enzymes to cleave the interstitial collagens may explain the anti-CII-associated joint destruction apparent in early RA.
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Fransson, Moa, 1981-, et al.
(författare)
Engineered T regulatory cells target CNS and suppress active EAE upon intra nasal delivery
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proven beneficial. However, systemic administration of such cells may immunologically compromise the recipient and promote infections due to general immunosuppression. We hypothesized that Tregs can be equipped with a CNS-targeting receptor and be delivered intra-nasally to avoid systemic exposure. In the current investigation, CD4+ T cells were modified with a lentiviral vector system to express a myelin oligodendrocyte (MOG)-targeting receptor in trans with the FoxP3 gene that drives Treg differentiation. The genetically engineered Tregs demonstrated suppressive capacity in vitro and were then tested in the EAE model. Engineered Tregs localized to the brain and suppressed ongoing encephalomyelitis in vivo. Cured mice were rechallenged with an EAE-inducing inoculum but remained healthy. Cytokine profile of the brain reveled lower levels of effector cytokines in TregCAR treated mice and acordingly, reduced axonal damage was seen in these mice. In conclusion, CNS-specific Tregs were able to localize to the CNS and efficiently cure mice with ongoing EAE.
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Kerzeli, Iliana Kyriaki, et al.
(författare)
MALT1 inhibition suppresses T-cell dependent immune surveillance
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
MALT1 supports the development of natural regulatory T cells (Tregs), while protease-dead MALT1 (MALT1-PD) mice develop autoimmunity and an intrinsic capacity to reject syngeneic tumor transplantation. Herein, a small molecule inhibitor targeting MALT1 was developed and evaluated for potential use in Treg inhibition as part of a cancer immunotherapy strategy.In vitro, MALT1 inhibitor treatment inhibited the proteolytic cleavage of the MALT1 substrate HOIL1 in Jurkat cells and blocked IL-2 secretion by immune cells. Moreover, orally administrated MV088428 inhibited anti-CD3 induced IL-2 release in vivo. In vitro MALT1 inhibition selectively suppressed the proliferation of PBMC derived CD25+ FoxP3+ CD4+ T cells, while no direct effect was noted on the proliferation and viability of CD25- CD4+ T cells. In vivo, no evident anti-tumor effect as a monotherapy in the MB49 bladder cancer model was achieved and despite selective decrease of Treg frequencies in lymph nodes of tumor bearing animals, intratumoral Treg depletion was not observed. No synergistic anti-tumor effects were noted when MALT1 inhibitor was combined with anti-PD1 therapy, and concomitant treatment with MALT1 inhibitor abrogated the efficacy of anti-CTLA4 therapy. MALT1 inhibition had no impact on the frequencies of viable NK, lymphocyte and myeloid cells or on proliferation of conventional CD4 and CD8 T cells. However, there was a significant decrease of antigen-specific T cells in vivo upon adoptive T cell transfer and peptide vaccination. Thus, while MALT1 inhibition substantially reduced Treg populations in lymph nodes, but less so in tumors, off-target effects on antigen-experienced T cells along with the lack of impact on tumor Tregs likely abolish the compound’s efficacy. The off-target effect on antigen-experienced T cells could present implications for the use of MALT1 inhibitors for cancer indications where tumor control is likely to be mediated via T cell driven immune surveillance. Thus, dosing length and combination therapy strategies should be carefully designed and evaluated further.
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Lomei, Jalal, 1980-, et al.
(författare)
Characterization of pro-angiogenic neutrophils
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
The roles of neutrophils in immune defense have been investigated for decades. These cells are well equipped to protect the body in several ways against invaders such as microorganism. Recently it has been reported that neutrophils also contribute to angiogenesis; they are recruited to the site of hypoxia where they can promote blood vessel formation, as demonstrated both in vivo and in vitro. We found that these neutrophils with proangiogenic actions form a specific subset of the circulating neutrophils. The proangiogenic neutrophils (PANs) exclusively express the adhesion molecule CD49d and vascular endothelial growth factor receptor 1 (VEGFR1), and contribute to angiogenesis by delivering MMP-9 (matrix metalloproteinase 9). In this study, PANs were compared to classic neutrophils in respect to physical features as well as functionality. We found that PANs in humans were smaller and in human and mice PANs had higher granularity compared to the classic neutrophils. Moreover, they were more efficient phagocytes than classic neutrophils. In the aortic ring model of angiogenesis, vessel neo-formation was increased by the presence of pro-angiogenic neutrophils. Finally, by using neutrophils from mice with impaired VEGFR1 receptor (Flt-1 tk-/- mice) we demonstrated the role of VEGFR1 in neutrophil recruitment towards angiogenic endothelium. Together these results show clear differences between the pro-angiogenic subpopulation and the classic neutrophils, which further solidify the conclusion of a specific neutrophil subpopulation.
