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Thymic retention of CD4+CD25+FoxP3+ T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia

Aslam, Rukhsana; Hu, Yu; Gebremeskel, Simon; Segel, George B; Speck, Edwin R; Guo, Li LU ; Kim, Michael; Ni, Heyu; Freedman, John and Semple, John W LU (2012) In Blood 120(10). p.32-2127
Abstract

Immune thrombocytopenia (ITP) is a bleeding disorder in which antibodies and/or T cells lead to enhanced peripheral platelet destruction and reduced bone marrow platelet production. Several reports have observed that ITP is associated with a peripheral deficiency of tolerance-inducing CD4+CD25+FoxP3+ T regulatory cells (Tregs). Using a murine model of ITP, we analyzed Tregs in the spleen and thymus. CD61 knockout mice were immunized against wild-type (CD61+) platelets, and their splenocytes were transferred into severe combined immunodeficient (SCID) mice. Compared with SCID mice receiving naive splenocytes, within 2 weeks after transfer, the ITP SCID mice became thrombocytopenic (< 200 × 10(9) platelets/L) and had increased serum... (More)

Immune thrombocytopenia (ITP) is a bleeding disorder in which antibodies and/or T cells lead to enhanced peripheral platelet destruction and reduced bone marrow platelet production. Several reports have observed that ITP is associated with a peripheral deficiency of tolerance-inducing CD4+CD25+FoxP3+ T regulatory cells (Tregs). Using a murine model of ITP, we analyzed Tregs in the spleen and thymus. CD61 knockout mice were immunized against wild-type (CD61+) platelets, and their splenocytes were transferred into severe combined immunodeficient (SCID) mice. Compared with SCID mice receiving naive splenocytes, within 2 weeks after transfer, the ITP SCID mice became thrombocytopenic (< 200 × 10(9) platelets/L) and had increased serum anti-CD61 antibodies. The quantity of thymic Tregs by 2 weeks after transfer was significantly elevated, whereas Tregs in the spleens were significantly reduced. Treatment of the ITP mice with 2 g/kg intravenous immunoglobulin raised the platelet counts, reduced antibody production, and normalized the thymic and splenic Treg populations. Compared with thymocytes from ITP mice treated with intravenous immunoglobulin, thymocytes from untreated ITP mice delayed the onset of ITP when administered before engraftment with immune splenocytes. These results suggest that ITP in mice is associated with a peripheral Treg deficiency because of thymic retention and therapy normalizes the Tregs.

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publishing date
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publication status
published
keywords
Animals, Antibodies, Blood Platelets, CD4 Lymphocyte Count, Disease Models, Animal, Female, Forkhead Transcription Factors, Immune System Diseases, Immunoglobulins, Intravenous, Integrin beta3, Interleukin-2 Receptor alpha Subunit, Lymphocyte Transfusion, Mice, Mice, Knockout, Mice, SCID, Organ Specificity, Spleen, T-Lymphocytes, Regulatory, Thrombocytopenia, Thymus Gland, Journal Article
in
Blood
volume
120
issue
10
pages
6 pages
publisher
American Society of Hematology
external identifiers
  • Scopus:84866177904
ISSN
1528-0020
DOI
10.1182/blood-2012-02-413526
language
English
LU publication?
no
id
9db5f898-9367-4f19-85e1-a777e0940d9b
date added to LUP
2016-09-23 12:03:15
date last changed
2017-01-29 04:32:34
@article{9db5f898-9367-4f19-85e1-a777e0940d9b,
  abstract     = {<p>Immune thrombocytopenia (ITP) is a bleeding disorder in which antibodies and/or T cells lead to enhanced peripheral platelet destruction and reduced bone marrow platelet production. Several reports have observed that ITP is associated with a peripheral deficiency of tolerance-inducing CD4+CD25+FoxP3+ T regulatory cells (Tregs). Using a murine model of ITP, we analyzed Tregs in the spleen and thymus. CD61 knockout mice were immunized against wild-type (CD61+) platelets, and their splenocytes were transferred into severe combined immunodeficient (SCID) mice. Compared with SCID mice receiving naive splenocytes, within 2 weeks after transfer, the ITP SCID mice became thrombocytopenic (&lt; 200 × 10(9) platelets/L) and had increased serum anti-CD61 antibodies. The quantity of thymic Tregs by 2 weeks after transfer was significantly elevated, whereas Tregs in the spleens were significantly reduced. Treatment of the ITP mice with 2 g/kg intravenous immunoglobulin raised the platelet counts, reduced antibody production, and normalized the thymic and splenic Treg populations. Compared with thymocytes from ITP mice treated with intravenous immunoglobulin, thymocytes from untreated ITP mice delayed the onset of ITP when administered before engraftment with immune splenocytes. These results suggest that ITP in mice is associated with a peripheral Treg deficiency because of thymic retention and therapy normalizes the Tregs.</p>},
  author       = {Aslam, Rukhsana and Hu, Yu and Gebremeskel, Simon and Segel, George B and Speck, Edwin R and Guo, Li and Kim, Michael and Ni, Heyu and Freedman, John and Semple, John W},
  issn         = {1528-0020},
  keyword      = {Animals,Antibodies,Blood Platelets,CD4 Lymphocyte Count,Disease Models, Animal,Female,Forkhead Transcription Factors,Immune System Diseases,Immunoglobulins, Intravenous,Integrin beta3,Interleukin-2 Receptor alpha Subunit,Lymphocyte Transfusion,Mice,Mice, Knockout,Mice, SCID,Organ Specificity,Spleen,T-Lymphocytes, Regulatory,Thrombocytopenia,Thymus Gland,Journal Article},
  language     = {eng},
  month        = {09},
  number       = {10},
  pages        = {32--2127},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Thymic retention of CD4+CD25+FoxP3+ T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia},
  url          = {http://dx.doi.org/10.1182/blood-2012-02-413526},
  volume       = {120},
  year         = {2012},
}