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Generation and application of antigen-specific induced regulatory t cells in allogeneic bone marrow transplantation

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Material Information

Title:
Generation and application of antigen-specific induced regulatory t cells in allogeneic bone marrow transplantation
Physical Description:
Book
Language:
English
Creator:
Semple, Kenrick
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla
Publication Date:

Subjects

Subjects / Keywords:
Allogeneic Stem Cell Transplantation
Cd28 Costimulation
Cd28-mediated Lck Signaling
Graft-versus-host-disease
Linked Suppression
Dissertations, Academic -- Immunology -- Doctoral -- USF   ( lcsh )
Genre:
bibliography   ( marcgt )
non-fiction   ( marcgt )

Notes

Abstract:
ABSTRACT: CD28 co-stimulation is required for the generation of naturally occurring regulatory T cells (nTregs) in the thymus through Lck-signaling. However, high level of CD28 suppresses the generation of induced Tregs (iTregs) from naïve CD4 T cells, although underlying mechanism(s) has not been defined. Here we investigated the role of CD28-mediated signaling pathways in the suppression of Treg generation. We used a series of transgenic (Tg) mice on CD28-deficient background that bears WT CD28 or mutated CD28 in its cytosolic tail incapable of binding to Lck, PI3K or Itk. Regardless of exogenous IL-2, strong CD28 costimulation suppressed iTreg generation through Lck signaling. Using a GVHD model to test the role of CD28-mediated iTreg suppression in T cell pathogenicity in vivo, we found that CD28-Lck T cells induced significantly less GVHD than T cells from CD28-WT mice. Furthermore, we found that the recipients of T cells from CD28-Lck mice generated significantly more iTregs than those with T cells from CD28-WT, which contribute to reduced graft-versus-host disease (GVHD) development in recipients of CD28-Lck T cells. These results indicate that CD28 costimulation can negatively regulate Treg generation and may provide an avenue for control of T-cell immunity or tolerance by regulating Tregs using the CD28 signal as a target. We went a step forward and investigated the therapeutic potential of antigen-specific iTregs in the prevention of GVHD. Donor hematopoietic stem cells and mature T cells are transplanted into a lymphopenic host to potentially cure many cancers and hematopoietic diseases like leukemia in bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HCT), but the frequent development of GVHD is the main drawback of this treatment. nTregs suppress the development of GVHD and may spare graft-versus-tumor effect. However, nTregs are a minor (~5%) subpopulation of CD4 helper T cells in healthy individuals, and using in vitro expanded nTregs is a common strategy to test their therapeutic potential in BMT. The concern of in vitro expanded nTregs may include their stability of Foxp3 (master regulatory gene for the development and function of regulatory T cell) expression and suppressive function, survival in vivo, and the non-selective suppression of the pre-activated nTregs. Antigen-specific activation of the regulatory T cells is important for optimal function. In this study, we used an alternative strategy to generate antigen-specific, iTregs and assessed their suppressive potential by comparing their effectiveness in preventing GVHD with polyclonal iTregs. We found that antigen-specific iTregs prevented GVHD lethality in recipients that expressed the target antigen, but were not protective of recipients who did not express the target antigen. Furthermore, antigen-specific iTregs were significantly more efficient than those polyclonal Tregs in the prevention of GVHD. These results reveal the therapeutic potential of antigen-specific iTregs to prevent GVHD efficiently and selectively, and provide the rationale to use antigen-specific iTregs in clinical HCT.
Thesis:
Disseration (Ph.D.)--University of South Florida, 2011.
Bibliography:
Includes bibliographical references.
System Details:
Mode of access: World Wide Web.
System Details:
System requirements: World Wide Web browser and PDF reader.
Statement of Responsibility:
by Kenrick Semple.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 117 pages.
General Note:
Includes vita.

Record Information

Source Institution:
University of South Florida Library
Holding Location:
University of South Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
usfldc doi - E14-SFE0004892
usfldc handle - e14.4892
System ID:
SFS0028148:00001


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PAGE 99

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PAGE 100

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PAGE 101

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PAGE 102

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PAGE 103

n 0nQnAnnn 4r9 )*(-*n*+ n?nn#!!&n 6 35Onn&&)#n nrnQMnnn )*(-*+ % +6r nQn-n4rn#!!&n ( 35Onn(0)#&n &n
PAGE 104

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PAGE 105

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PAGE 106

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PAGE 107

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PAGE 108

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PAGE 109

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PAGE 110

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PAGE 111

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PAGE 113

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PAGE 114

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PAGE 115

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PAGE 116

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PAGE 117

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Semple, Kenrick
0 245
Generation and application of antigen-specific induced regulatory t cells in allogeneic bone marrow transplantation
h [electronic resource] /
by Kenrick Semple.
260
[Tampa, Fla] :
b University of South Florida,
2011.
500
Title from PDF of title page.
Document formatted into pages; contains 117 pages.
Includes vita.
502
Disseration
(Ph.D.)--University of South Florida, 2011.
504
Includes bibliographical references.
516
Text (Electronic dissertation) in PDF format.
3 520
ABSTRACT: CD28 co-stimulation is required for the generation of naturally occurring regulatory T cells (nTregs) in the thymus through Lck-signaling. However, high level of CD28 suppresses the generation of induced Tregs (iTregs) from nave CD4 T cells, although underlying mechanism(s) has not been defined. Here we investigated the role of CD28-mediated signaling pathways in the suppression of Treg generation. We used a series of transgenic (Tg) mice on CD28-deficient background that bears WT CD28 or mutated CD28 in its cytosolic tail incapable of binding to Lck, PI3K or Itk. Regardless of exogenous IL-2, strong CD28 costimulation suppressed iTreg generation through Lck signaling. Using a GVHD model to test the role of CD28-mediated iTreg suppression in T cell pathogenicity in vivo, we found that CD28-Lck T cells induced significantly less GVHD than T cells from CD28-WT mice. Furthermore, we found that the recipients of T cells from CD28-Lck mice generated significantly more iTregs than those with T cells from CD28-WT, which contribute to reduced graft-versus-host disease (GVHD) development in recipients of CD28-Lck T cells. These results indicate that CD28 costimulation can negatively regulate Treg generation and may provide an avenue for control of T-cell immunity or tolerance by regulating Tregs using the CD28 signal as a target. We went a step forward and investigated the therapeutic potential of antigen-specific iTregs in the prevention of GVHD. Donor hematopoietic stem cells and mature T cells are transplanted into a lymphopenic host to potentially cure many cancers and hematopoietic diseases like leukemia in bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HCT), but the frequent development of GVHD is the main drawback of this treatment. nTregs suppress the development of GVHD and may spare graft-versus-tumor effect. However, nTregs are a minor (~5%) subpopulation of CD4 helper T cells in healthy individuals, and using in vitro expanded nTregs is a common strategy to test their therapeutic potential in BMT. The concern of in vitro expanded nTregs may include their stability of Foxp3 (master regulatory gene for the development and function of regulatory T cell) expression and suppressive function, survival in vivo, and the non-selective suppression of the pre-activated nTregs. Antigen-specific activation of the regulatory T cells is important for optimal function. In this study, we used an alternative strategy to generate antigen-specific, iTregs and assessed their suppressive potential by comparing their effectiveness in preventing GVHD with polyclonal iTregs. We found that antigen-specific iTregs prevented GVHD lethality in recipients that expressed the target antigen, but were not protective of recipients who did not express the target antigen. Furthermore, antigen-specific iTregs were significantly more efficient than those polyclonal Tregs in the prevention of GVHD. These results reveal the therapeutic potential of antigen-specific iTregs to prevent GVHD efficiently and selectively, and provide the rationale to use antigen-specific iTregs in clinical HCT.
538
Mode of access: World Wide Web.
System requirements: World Wide Web browser and PDF reader.
590
Advisor:
Yu Kruk, Xue-Zhong Patricia .
Advisor:
Yu Kruk, Xue-Zhong Patricia .
653
Allogeneic Stem Cell Transplantation
Cd28 Costimulation
Cd28-mediated Lck Signaling
Graft-versus-host-disease
Linked Suppression
690
Dissertations, Academic
z USF
x Immunology
Doctoral.
773
t USF Electronic Theses and Dissertations.
4 856
u http://digital.lib.usf.edu/?e14.4892