scholarly journals Steady-State Cell Apoptosis and Immune Tolerance - Induction of Tolerance Using Apoptotic Cells in Type 1 Diabetes and Other Immune-Mediated Disorders

10.5772/22113 ◽  
2011 ◽  
Author(s):  
Chang-Qing Xia ◽  
Kim Campbell ◽  
Benjamin Keselowsky ◽  
Michael Clare-Salzler
Keyword(s):  
Type 1 Diabetes ◽  
Steady State ◽  
Immune Tolerance ◽  
Cell Apoptosis ◽  
Tolerance Induction ◽  
Apoptotic Cells ◽  
Immune Tolerance Induction ◽  
Immune Mediated ◽  
Induction Of Tolerance

Prevention of Inhibitor Development Using Apoptosis-Induced FVIII Producing ES Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3381-3381
Author(s):  
Shogo Kasuda ◽  
Yoshihiko Sakurai ◽  
Kohei Tatsumi ◽  
Tomohiro Takeda ◽  
Atsushi Kubo ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Es Cells ◽  
Tolerance Induction ◽  
Target Protein ◽  
Apoptotic Cells ◽  
Danger Signal ◽  
Immune Tolerance Induction ◽  
Peptide Epitopes ◽  
Inhibitor Titer

Abstract [Background] Hemophilia A is an X-linked bleeding disorder resulting from abnormality in the coagulation factor VIII (FVIII) gene. Development of inhibitors remains a significant problem for a treatment of hemophilia A. Approximately 25–30% of sever type hemophilia A patients develop inhibitor antibodies that reduce or completely negate the benefits of replacement therapy. Furthermore, a major issue that all gene therapy trials for hemophilia are facing is the risk of forming inhibitory antibodies to the transgene product. Although immune tolerance induction (ITI) is the effective method to decrease inhibitor concentration, it costs too expensively and there are some patients who do not show any response to ITI. Thus, it is desired to establish a novel immune tolerance induction method. Recent immunological studies have pointed out that “danger signal” is required to initiate immune reactions and immune tolerance is induced in the absence of danger signal. Apoptotic cell death is considered to be associated with immune tolerance because processing of intracellular antigen occurs without danger signal. Recently, Miyake et al. reported that intravenous injection of apoptotic cells expressing a fragment of myelin oligodendrocyte glycoprotein (MOG) on cell membrane reduced MOG-specific T cell response and prevented the development of experimental autoimmune encephalomyelitis (EAE) [J Clin Invest2007;117:2268–78.]. Based on these principles and findings, we investigated the novel immune tolerance approach with pretreatment of apoptotic embryonic stem (ES) cells secreting FVIII. [Methods] All animal experiments were performed in accordance with institutional and national regulations and approved by the Nara Medical University Animal Care Committee. We have already established mouse ES cells secreting human FVIII by integrating human FVIII gene [Kasuda et al, J Thromb Haemost 2008]. As a pretreatment, hypo-osmotic stress-induced apoptotic ES cells were injected intraperitoneally into the FVIII-KO mouse. After the various periods, administration of hFVIII concentrates (4 IU/body) was repeated every week. Then, titration of inhibitor was measured chronologically with Bethesda methods. [Results] In the non-pretreatment group (n=15), the inhibitor titer was 0.03 ± 0.00 BU/ml at 1 week after first administration of hFVIII concentrates. Then, the inhibitor titer rose to 0.18 ± 0.03 BU/ml and 3.03 ± 0.12 BU/ml with every following hFVIII administration. On the other hand, in the pretreatment group #1 (hFVIII administration was begun 1 week after pretreatment, n=9), inhibitor titer showed the significantly low levels (0.54 ± 0.27 BU/ml) even after thrice administration of hFVIII (p<0.05). Furthermore, in another pretreatment group #2 (hFVIII administration was begun 2 weeks after pretreatment, n=3), inhibitor titer showed much lower levels (0.09 ± 0.03 BU/ml) after thrice administration (p<0.01). [Discussion] We showed the possibility of reduction of inhibitor titer with pretreatment of apoptotic hFVIII secreting ES cells. The efficacy for the reduction of inhibitor titer depended on the period between pretreatment with apoptotic cells and first hFVIII administration, suggesting that a specified period is required to induce immune tolerance. Unlike the method using a peptide fragment of target protein (MOG) in the previous report by Miyake et al., our method features the utilization of a whole target protein (FVIII), by which tolerance to multiple epitopes of the protein would be induced. Identification of the precise peptide epitopes of a target protein would not be necessary since selection and presentation are executed by the host’s own antigen presenting cells. We aspire for the complete suppression of inhibitor formation with an ingenious administration of apoptotic ES cells. We believe that this approach has potential for future clinical therapy.

Low-dose Immune Tolerance Induction in Hemophilia

2019 ◽  
Vol 41 (6) ◽  
pp. e355-e358 ◽  
Author(s):  
Bulent Zulfikar ◽  
Basak Koc ◽  
Nihal Ozdemir
Keyword(s):  
Immune Tolerance ◽  
Low Dose ◽  
Tolerance Induction ◽  
Immune Tolerance Induction

Benefits of prophylactic emicizumab in enhancing immune tolerance induction in a boy with hemophilia A and very high inhibitor titer

2021 ◽  
Author(s):  
Nongnuch Sirachainan ◽  
Ampaiwan Chuansumrit ◽  
Surapan Parapakpenjune ◽  
Pakawan Wongwerawattanakoon ◽  
Surapong Lertthammakiat ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Inhibitor Titer ◽  
Very High

scholarly journals TLR9-Deficiency in B Cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

Diabetes ◽  
2020 ◽  
pp. db200373
Author(s):  
Sha Sha ◽  
James A Pearson ◽  
Jian Peng ◽  
Youjia Hu ◽  
Juan Huang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
Mouse Model ◽  
Immune Tolerance ◽  
Diabetes Mouse

scholarly journals IgG subclasses of anti-FVIII antibodies during immune tolerance induction in patients with hemophilia A

2008 ◽  
Vol 142 (4) ◽  
pp. 644-652 ◽  
Author(s):  
Pauline M. W. van Helden ◽  
H. Marijke van den Berg ◽  
Samantha C. Gouw ◽  
Paul H. P. Kaijen ◽  
Marleen G. Zuurveld ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Igg Subclasses ◽  
Immune Tolerance Induction
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