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Heparins in immunology and the immunology of heparins
Abstracts / Journal of Reproductive Immunology 81 (2009) 113–175
133
shown by the increased prevalence of HPV infections and HGSIL in individuals immunosuppressed as a consequence of HIV infection. The prolonged duration of infection associated with HPV seems to be associated with effective evasion of innate immunity as reflected in the absence of inflammation during virus replication, assembly and release, and down regulation of interferon secretion and response thus delaying the activation of adaptive immunity. Serum neutralising antibody to the major capsid protein L1 usually develops after the induction of successful cell mediated immunity and these antibody and cell mediated responses are protective against subsequent viral challenge in natural infections in animals. Prophylactic vaccines consisting of HPV L1 VLPs generate high anti L1 serum neutralizing antibody concentrations and in clinical trials have shown greater than 95% efficacy against both benign and neoplastic genital HPV associated disease. These vaccines are delivered intramuscularly and therefore circumvent the immune evasion strategies of the virus.
discontinued 24 h before induction of labor or planned Caesarean Section and, in most cases, restarted 12 h post delivery. The management of women with prosthetic heart valves requiring anticoagulation in pregnancy remains controversial. Women treated with LMWHs can safely breastfeed. Heparin and related compounds have also anti-inflammatory actions, showing potential Clinical Benefit in patients with bronchial asthma, ulcerative colitis and burns, inhibiting IFN-␥ responses or disrupting specific Th1 cell trafficking. Furthermore, heparin has been shown to possess renoprotective action in experimental nephropathies, by decreasing glomerular TNF-␣ production. At the molecular level, there is evidence that heparin and related compounds may exert antiinflammatory effects through the transcription factor NF-B, inhibit gene expression and production of TNF-␣ and prevent P-selectin and integrin mediated recruitment of neutrophils. This review will try to highlight the multifactorial role of LMWH administration concerning immunology of reproduction.
doi:10.1016/j.jri.2009.06.170
doi:10.1016/j.jri.2009.06.171
L45 Heparins in immunology and the immunology of heparins
L46 Anti-TNF therapy in immune-mediated subfertility
M. Daniilidis Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Heparin is a highly sulfated polysaccharide composed of hexuronic acid and d-glucosamine residues, member of a family of polyanionic polysaccharides called glycosaminoglycans (GAGs). Ninety three years after its discovery, heparin remains one of the most important anticoagulant drugs in clinical practice. It is currently used for the treatment and prevention of deep-vein thrombosis and pulmonary embolism, arterial thrombosis, acute myocardial infarction, atrial fibrillation, extracorporeal circuits and hemodialysis. The mechanisms underlying the anticoagulant effects of heparin are considered nowadays to be well understood. Low molecular weight heparins (LMWHs), consisting of only short chains of polysaccharide, are obtained by various methods of fractionation of polymeric heparin. As they are associated with less bleeding complications, thrombocytopenia and osteoporosis, LMWHs are considered to be the anticoagulant of choice in pregnancies with increased risk of thrombosis, due to antiphospholipid syndrome (APS), acquired and/or inherited Thrombophilia or even the hypercoagulability of pregnancy. LMWHs should be
D.A. Clark a,b a
Departments of Medicine, Molecular Medicine & Pathology, Obstetrics & Gynecology, McMaster University, Hamilton, Canada b Toronto General Research Institute and Institute of Medical Sciences, University of Toronto, Ontario, Canada A sufficient concentration of the pro-inflammatory Th1type cytokine TNF-␣ in the presence of IFN-␥, can trigger loss of the implanted embryo in mouse models, and the peripheral blood CD3+ lymphocytes from a subset of women with recurrent unexplained miscarriages and/or infertility produce an excess of TNF-␣ and IFN-␥ with respect to IL-10, a Th2 cytokine able to prevent abortions in mouse models. In mouse models, anti-TNF-␣ therapy can abrogate pregnancy loss; in mice, TNF-␣ is not required for implantation or pregnancy success. Recently, two observational studies, one on recurrent miscarriage (RSA) patients and one on recurrent IVF-failure (RIVFF) patients have described improved live birth rates when anti-TNF-␣ was added to other treatments such as heparin + ASA ± IVIG. In RIVFF, the effect of adding anti-TNF-␣ (Humira® ) prior to conception (with no post-conception treatment) generated extraordinarily high pregnancy rates and a 70–80%
133
shown by the increased prevalence of HPV infections and HGSIL in individuals immunosuppressed as a consequence of HIV infection. The prolonged duration of infection associated with HPV seems to be associated with effective evasion of innate immunity as reflected in the absence of inflammation during virus replication, assembly and release, and down regulation of interferon secretion and response thus delaying the activation of adaptive immunity. Serum neutralising antibody to the major capsid protein L1 usually develops after the induction of successful cell mediated immunity and these antibody and cell mediated responses are protective against subsequent viral challenge in natural infections in animals. Prophylactic vaccines consisting of HPV L1 VLPs generate high anti L1 serum neutralizing antibody concentrations and in clinical trials have shown greater than 95% efficacy against both benign and neoplastic genital HPV associated disease. These vaccines are delivered intramuscularly and therefore circumvent the immune evasion strategies of the virus.
discontinued 24 h before induction of labor or planned Caesarean Section and, in most cases, restarted 12 h post delivery. The management of women with prosthetic heart valves requiring anticoagulation in pregnancy remains controversial. Women treated with LMWHs can safely breastfeed. Heparin and related compounds have also anti-inflammatory actions, showing potential Clinical Benefit in patients with bronchial asthma, ulcerative colitis and burns, inhibiting IFN-␥ responses or disrupting specific Th1 cell trafficking. Furthermore, heparin has been shown to possess renoprotective action in experimental nephropathies, by decreasing glomerular TNF-␣ production. At the molecular level, there is evidence that heparin and related compounds may exert antiinflammatory effects through the transcription factor NF-B, inhibit gene expression and production of TNF-␣ and prevent P-selectin and integrin mediated recruitment of neutrophils. This review will try to highlight the multifactorial role of LMWH administration concerning immunology of reproduction.
doi:10.1016/j.jri.2009.06.170
doi:10.1016/j.jri.2009.06.171
L45 Heparins in immunology and the immunology of heparins
L46 Anti-TNF therapy in immune-mediated subfertility
M. Daniilidis Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Heparin is a highly sulfated polysaccharide composed of hexuronic acid and d-glucosamine residues, member of a family of polyanionic polysaccharides called glycosaminoglycans (GAGs). Ninety three years after its discovery, heparin remains one of the most important anticoagulant drugs in clinical practice. It is currently used for the treatment and prevention of deep-vein thrombosis and pulmonary embolism, arterial thrombosis, acute myocardial infarction, atrial fibrillation, extracorporeal circuits and hemodialysis. The mechanisms underlying the anticoagulant effects of heparin are considered nowadays to be well understood. Low molecular weight heparins (LMWHs), consisting of only short chains of polysaccharide, are obtained by various methods of fractionation of polymeric heparin. As they are associated with less bleeding complications, thrombocytopenia and osteoporosis, LMWHs are considered to be the anticoagulant of choice in pregnancies with increased risk of thrombosis, due to antiphospholipid syndrome (APS), acquired and/or inherited Thrombophilia or even the hypercoagulability of pregnancy. LMWHs should be
D.A. Clark a,b a
Departments of Medicine, Molecular Medicine & Pathology, Obstetrics & Gynecology, McMaster University, Hamilton, Canada b Toronto General Research Institute and Institute of Medical Sciences, University of Toronto, Ontario, Canada A sufficient concentration of the pro-inflammatory Th1type cytokine TNF-␣ in the presence of IFN-␥, can trigger loss of the implanted embryo in mouse models, and the peripheral blood CD3+ lymphocytes from a subset of women with recurrent unexplained miscarriages and/or infertility produce an excess of TNF-␣ and IFN-␥ with respect to IL-10, a Th2 cytokine able to prevent abortions in mouse models. In mouse models, anti-TNF-␣ therapy can abrogate pregnancy loss; in mice, TNF-␣ is not required for implantation or pregnancy success. Recently, two observational studies, one on recurrent miscarriage (RSA) patients and one on recurrent IVF-failure (RIVFF) patients have described improved live birth rates when anti-TNF-␣ was added to other treatments such as heparin + ASA ± IVIG. In RIVFF, the effect of adding anti-TNF-␣ (Humira® ) prior to conception (with no post-conception treatment) generated extraordinarily high pregnancy rates and a 70–80%