Alloimmune and Autoimmune Background in Recurrent Pregnancy Loss – Successful Immunotherapy by Intravenous Immunoglobulin

Kotlan, Beatrix; Padányi, Á; Bátorfi, József; Fülöp, Vilmos; Szigetvári, Iván; Rajczy, Katalin; Penzes, Maria; Gyódi, É; Reti, Marienne; Petrányi, G

doi:10.1111/j.1600-0897.2006.00368.x

Cited by 22 publications

(13 citation statements)

References 35 publications

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“…However, many clinical studies where IVIG were given to women suffering from recurrent spontaneous abortions, a noninflammatory condition, reported the opposite results, ie, decreased NK cell cytolytic activity and/or decreased number or percentage of circulating NK cells in treated women [35][36][37][38][39][41][42][43][44]. These discrepancies could be explained by the various conditions in which IVIG are used and, particularly, the existence or not of an inflammatory state.…”

Section: Discussionmentioning

confidence: 77%

“…Until recently, the possible role of NK cells in mediating the immunomodulatory effect of IVIG had never been mentioned. On the contrary, it was suggested that for preventing miscarriage, IVIG could act by inhibiting NK cells [35][36][37][38][39][40][41][42][43][44]. However, very recently, Chong et al [45] elegantly demonstrated that NK cells are necessary for the prevention of experimental autoimmune encephalomyelitis (EAE) by IVIG treatment.…”

Section: Discussionmentioning

confidence: 92%

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Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Gregoire-Gauthier

Fontaine

Benchimol

et al. 2015

Biology of Blood and Marrow Transplantation

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Although clinical studies have yet to demonstrate clearly the use of intravenous immunoglobulin (IVIG) for prevention of graft-versus-host disease (GVHD), their effective use in a xenogeneic mouse model has been demonstrated. We aimed to determine the mechanism of action by which IVIG contributes to GVHD prevention in a xenogeneic mouse model. NOD/LtSz-scidIL2rg(-/-) (NSG) mice were used for our xenogeneic mouse model of GVHD. Sublethally irradiated NSG mice were injected with human peripheral blood mononuclear cells (huPBMCs) and treated weekly with PBS or 50 mg IVIG. Incidence of GVHD and survival were noted, along with analysis of cell subsets proliferation in the peripheral blood. Weekly IVIG treatment resulted in a robust and consistent proliferation of human natural killer cells that were activated, as demonstrated by their cytotoxicity against K562 target cells. IVIG treatment did not inhibit GVHD when huPBMCs were depleted in natural killer (NK) cells, strongly suggesting that this NK cell expansion was required for the IVIG-mediated prevention of GVHD in our mouse model. Moreover, inhibition of T cell activation by either cyclosporine A (CsA) or monoclonal antihuman CD3 antibodies abolished the IVIG-induced NK cell expansion. In conclusion, IVIG treatment induces NK cell proliferation, which is essential for IVIG-mediated protection of GVHD in our mouse model. Furthermore, activated T cells are mandatory for effective IVIG-induced NK cell proliferation. These results shed light on a new mechanism of action of IVIG and could explain why the efficacy of IVIG in preventing GVHD in a clinical setting, where patients receive CsA, has never been undoubtedly demonstrated.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 92%

Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Gregoire-Gauthier

Fontaine

Benchimol

et al. 2015

Biology of Blood and Marrow Transplantation

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“…Immunoglobulin therapy has been shown to be clinically beneficial in some selected groups of women with RPL by reducing NK cell cytotoxicity or favorably decreasing Th1/Th2 ratios (52)(53)(54). Our preliminary data revealed that the immunoglobulin therapy was effective for decreasing pregnancy loss in Sphk1…”

Section: Sphk2mentioning

confidence: 69%

Sphingolipid Pathway Regulates Innate Immune Responses at the Fetomaternal Interface during Pregnancy

Mizugishi

Inoue²,

Hatayama³

et al. 2015

Journal of Biological Chemistry

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Background: Mechanisms by which the mother does not reject the fetus are not fully understood. Results: In sphingosine kinase-deficient mice, the innate arm of the maternal immune system attacks the fetus, resulting in miscarriage. Conclusion: Sphingolipid metabolism has an essential role in maternal immunological adaptation to the fetus. Significance: Our findings may help to develop treatments for unexplained miscarriages in humans.

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“…This study revealed that RSA patient show high total capacity of iron bounding in peripheral blood and a HLA class I mismatch, a high cytotoxic potential that may be associated with the lack of erythrocytes antibody inhibition-blocking antibody, that appeared after IVIG therapy and were associated with the continuation of the pregnancies [93].…”

Section: Nk Cells and High Doses Intravenous Immunoglobulinsmentioning

confidence: 97%

NK Cells, Autoantibodies, and Immunologic Infertility: A Complex Interplay

Carolis

Perricone

2009

Clinic Rev Allerg Immunol

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Infertility and recurrent spontaneous abortion (RSA) are heterogeneous conditions that have been frequently explained with an immunological pathomechanism. A deeper insight into apparently unexplained infertility and RSA shows increasing evidences supporting both alloimmune and autoimmune mechanisms, in which natural killer (NK) cells and autoantibodies seem to play a relevant role. Successful pregnancy is considered as Th1-Th2 cooperation phenomenon, with a predominantly Th2-type lymphocytes response, together with the emerging role of interleukin (IL)-12, IL-15, and IL-18 and of other unidentified soluble factors dependent on NK cells. Uterine NK cells comprise the largest population at implantation site, and their activity, characteristics, and abundance suggest that they participate at the "decidualization" process that, vice versa, induces NK activation and recruitment in each menstrual cycle. However, NK cell alteration may be associated with impaired pregnancy, and the modulation in the number of circulating NK cells is most likely to be a primary event rather than an active inflammation/drug administration consequence during an inflammatory/autoimmune process, thus playing an important role in the pathogenesis of immunological infertility. Relationships within immunological infertility, recurrent spontaneous abortion, autoantibodies, and NK cells will be reviewed herein.

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Alloimmune and Autoimmune Background in Recurrent Pregnancy Loss – Successful Immunotherapy by Intravenous Immunoglobulin

Abstract: The novel cellular immunological assays proved to be favourable for the indication of RSA patients and showed the usefulness of this selection process for effective immunotherapy.

Cited by 22 publications

References 35 publications

Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Sphingolipid Pathway Regulates Innate Immune Responses at the Fetomaternal Interface during Pregnancy

NK Cells, Autoantibodies, and Immunologic Infertility: A Complex Interplay

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