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The Role of Regulatory T Cells Expanded by Anti-DR3 Antibody for Alleviation of Acute Graft-versus-Host Disease : 급성 이식편대숙주질환 완화를 위한 항 DR3 항체에 의해 증가된 조절 T 세포의 역할
DC Field | Value | Language |
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dc.contributor.advisor | 박정규 | - |
dc.contributor.author | 김병수 | - |
dc.date.accessioned | 2017-07-14T01:30:50Z | - |
dc.date.available | 2017-07-14T01:30:50Z | - |
dc.date.issued | 2015-02 | - |
dc.identifier.other | 000000025162 | - |
dc.identifier.uri | https://hdl.handle.net/10371/122047 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2015. 2. 박정규. | - |
dc.description.abstract | Introduction: Regulatory T cells (Treg) alleviate acute graft-versus- host disease (aGVHD) while preserving graft-versus-tumor (GVT) effects. However, their low frequency hinders clinical translation. Although a lot of protocols to expand Treg have been reported, they still have limitations. DR3 belongs to the TNF receptor superfamily and is expressed primarily on T cells. Its agonistic antibody (Ab) was reported to expand Treg in vivo and prevent the rejection of a cardiac allograft. Methods: C57BL/6 donor mice were intraperitoneally injected with anti-DR3 Ab or hamster IgG isotype control and conventional T cells (Tcon) were isolated from them four days later. Tcon and T cell- depleted (TCD) bone marrow (BM) cells were transplanted to lethally irradiated Balb/c recipients. Clinical signs of aGVHD and bioluminescence imaging (BLI) were regularly monitored. Recipient mice were sacrificed for flow cytometric analyses and serum cytokine assay at predefined time points.
Results: Donor mice treated with anti-DR3 Ab yielded Tcon containing higher proportions of Treg that suppressed Tcon proliferation with lower numbers. Mixed lymphocyte reaction (MLR) showed that these Tcon maintained higher Treg proportions, were less proliferative, had reduced Th1 differentiation and more PD-1 expression on Treg in response to allogeneic stimuli. In vivo studies confirmed that Tcon from anti-DR3-treated mice expanded to a lesser extent and caused the reduced aGVHD. Treg from anti-DR3-treated donors expanded robustly and their proportions within donor CD4+ T cells were maintained higher. CD25 expression and BrdU incorporation of non-Treg CD4+ and CD8+ T cells derived from anti-DR3-treated donors were reduced in vivo. Recipients of Tcon from anti-DR3-treated donors had lower serum IFNγ, IL-1β, and TNFα levels. Tcon from anti-DR3-treated donors also preserved their GVT effects. Conclusions: Together these data suggest that treating donors with anti-DR3 Ab can effectively expand donor Treg, alleviate aGVHD and preserve GVT effects. Conclusively, anti-DR3 Ab could be utilized as one of the strategies for in situ expansion of regulatory T cells. | - |
dc.description.tableofcontents | Introduction 1
What is aGVHD 1 How to control aGVHD 1 Control of aGVHD by natural Treg 2 Expansion of natural Treg and its limitations 3 Use of induced Treg (iTreg) and T regulatory type 1 (Tr1) cells 3 Death receptor 3 (DR3, TNFRSF25) 4 Treg expansion by DR3 stimulation 5 Materials and Methods 6 Mice and cell line 6 Antibodies and reagents 6 Cell isolation/sorting after Ab administration 7 Mouse models: MHC I/II-mismatch aGVHD and BCL1 tumor models 7 Mixed lymphocyte reaction (MLR) 8 Flow cytometric analysis: Foxp3, cytokines and BrdU staining 9 In vivo bioluminescence imaging (BLI) 9 Multiplex cytokine assays 10 Statistical analysis 10 Results 11 Tcon isolated from anti-DR3-treated mice contain higher proportion of Treg that are functional with lower numbers 11 Tcon from anti-DR3-treated donors are less proliferative, less activated and maintain higher Treg level in MLR 12 Tcon from anti-DR3-treated donors expand poorly in vivo and cause reduced aGVHD mortality and morbidity 13 Treg from anti-DR3-treated donors expand robustly after BMT and suppress Tcon proliferation in vivo 14 Tcon from anti-DR3-treated donors down-regulate CD25 and cause lower serum inflammatory cytokines 15 Tcon from anti-DR3-treated donors retain GVT effects 16 Discussion 18 DR3 stimulation results in sustainably higher donor Treg frequency, which is important for aGVHD control 18 DR3 stimulation causes prolonged reduction of serum TNFα, the important effector cytokine of aGVHD 19 DR3-stimulated Treg do not interfere with GVT effects 20 Conclusion: administration of anti-DR3 Ab can be easily translated to clinical trials 21 Table 1 23 Figure Legends 24 Figure 1: Scheme of BM transplantation using anti-DR3 treated B6 donor mice 24 Figure 2: Expanded Treg isolated from anti-DR3-treated mice and their suppressive activity 24 Figure 3: Tcon from anti-DR3-treated mice are less proliferative, less activated and maintain higher Treg level 25 Figure 4: Recipients of Tcon from anti-DR3-treated donors have reduced Tcon expansion and longer survival 25 Figure 5: Increased Treg expansion but decreased proliferation of Tcon derived from anti-DR3-treated donors 26 Figure 6: Surface CD25 expression of non- Treg T cells and serum levels of inflammatory cytokines 27 Figure 7: Treg proportions, proliferation of donor-derived Tcon and serum cytokines for the later phase of aGVHD 27 Figure 8. Tcon from anti-DR3-treated donors retain GVT effects 28 Figures 29 Figure 1 29 Figure 2 30 Figure 3 31 Figure 4 33 Figure 5 36 Figure 6 37 Figure 7 38 Figure 8 40 References 42 국문초록 48 | - |
dc.format | application/pdf | - |
dc.format.extent | 7211138 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | acute graft-versus-host disease | - |
dc.subject | bone marrow transplantation | - |
dc.subject | regulatory T cells | - |
dc.subject | DR3 | - |
dc.subject.ddc | 610 | - |
dc.title | The Role of Regulatory T Cells Expanded by Anti-DR3 Antibody for Alleviation of Acute Graft-versus-Host Disease | - |
dc.title.alternative | 급성 이식편대숙주질환 완화를 위한 항 DR3 항체에 의해 증가된 조절 T 세포의 역할 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Kim, Byung-Su | - |
dc.description.degree | Doctor | - |
dc.citation.pages | vii, 49 | - |
dc.contributor.affiliation | 의과대학 의학과 | - |
dc.date.awarded | 2015-02 | - |
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