Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation

Contributors

Foreword

Abbreviations

CH 1. Overview of the immune biology of allogeneic hematopoietic stem cell transplantation

Introduction

Immune rejection

Immune deficiency

GVHD pathophysiology

The graft-versus-leukemia effect

References

CH 2. The HLA system in hematopoietic stem cell transplantation

Introduction

Classical HLA

The role of classical HLA in unrelated donor hematopoietic cell transplantation

The clinical significance of non-classical HLA genes: HLA-E, (HLA-F), HLA-G and MIC genes

Conclusions

Acknowledgments

References

CH 3. The impact of minor histocompatibility antigens in allogeneic stem cell transplantation

From immunobiology to the impact of mHags in GVHD and GVT

Murine mHags, challenges for the human system

Immunobiology and biochemical identity of mHags

Mechanisms of generation of mHags

The impact of individual mHags on GVHD and GVT

To match or to mismatch: paradigm shifts in the mHag field

Hematopoietic mHags: ideal targets for separating GVT from GVHD

Immunotherapeutic targeting of hematopoietic mHags

Toward a broad and more effective application of mHag therapy

Controlling naturally existing and mHag-specific CD8+ regulatory T cells

Concluding remarks

References

CH 4. In vivo imaging of graft-versus-host disease and graft-versus-leukemia

Introduction

Bioluminescence imaging

In vivo fluorescence imaging

Nuclear imaging (PET/SPECT)

Magnetic resonance imaging

Multimodal imaging of GVHD and anti-tumor responses

Advances in imaging technology

Conclusion

References

CH 5. Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans)

Introduction

Hematopoietic space and microenvironment

Effector mechanisms of graft rejection

Impact of pretransplant conditioning on effector mechanisms of rejection

Impact of MHC-matching on risk of rejection – from mice to humans

Impact of donor cells on risk of rejection – from mice to humans

Impact of post-transplant immunosuppression on risk of rejection

Future directions

References

CH 6. Strategies to improve post-transplant immunity

Introduction

Post-transplant immune deficiency

GVHD of the thymus

Interleukin-7

Keratinocyte growth factor

Sex steroid ablation

Growth hormone

T-cell precursors

Interleukin-22

Flt3L

Other cytokines and growth factors

Conclusions

References

CH 7. Tumor-associated antigens

Introduction

Biology of tumor-associated antigens

Aberrantly expressed self-antigens

Tumor-specific antigens

Mutated self-antigens

Cellular approaches to targeting TAA

Unanswered questions

Conclusion

References

CH 8. Impact of the conditioning regimen

First evidence for a role of conditioning in pathophysiology of GVHD

Mechanisms of increased GVHD

Role of inflammation and damage to immunological organs

Controversies and alternative explanations

References

CH 9. Antigen presentation and antigen-presenting cells in graft-versus-host disease

Introduction

Major versus minor histocompatibility antigens

Direct versus indirect presentation of miHAs and cross-priming

The roles of host-derived hematopoietic and nonhematopoietic APCs in GVHD

Where does T-cell priming occur?

Priming independent of hematopoietic APCs (revisited)

Specific hematopoietic APC subtypes in GVHD

References

CH 10. T-cell costimulation in graft-versus-host disease and graft-versus-leukemia effect

Introduction

B7/CD28 superfamily

TNF/TNFR superfamily

Regulation of GVHD by costimulation through tregs

Conclusions

References

CH 11. Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation

T-helper differentiation

Experimental transplantation models evaluating the Th1/Th2 paradigm

Clinical transplantation and the Th1/Th2 paradigm

Future directions/unanswered questions

References

CH 12. Natural CD4+CD25+FOXP3+ regulatory T cells in graft-versus-host disease

Introduction

Treg biology

Treg in experimental SCT

Treg in clinical SCT

Summary

References

CH 13. Role of Th17 cells and interleukin 17 in graft-versus-host disease and graft-versus-leukemia reactivity

Discovery of Th17 cells

Differentiation and actions of Th17 cells

Interaction of Th17 cells with Th1, Th2, and Tregs

Role of IL-17 and Th17 cells in preclinical models of acute graft-versus-host disease

Role of IL-17 and Th17 cells in chronic GVHD

Roles of cytokines that induce Th17 differentiation in GVHD

Roles of transcription factors involved in Th17 cell differentiation in GVHD

Role of IL-17 and Th17 cells in clinical GVHD

Role of IL-17 and IL-23R polymorphisms in GVHD

Roles of other Th17 cytokines in GVHD biology

Role of IL-17 and Th17 cells in GVL reactivity

Summary

Unanswered questions

Acknowledgments

References

CH 14. B and T cells in chronic graft-versus-host disease and graft-versus-leukemia

Introduction

Chronic graft-versus-host disease

Graft-versus-leukemia and graft-versus-tumor effects of allogeneic transplantation

From pathogenesis to therapy: cGVHD and GVL/GVT

Conclusions

References

CH 15. Natural killer cells in graft-versus-host disease and graft-versus-leukemia

Introduction

NK cell receptors

NK cell signaling

Acquisition of NK cell function

NK cell memory

Role of NK cells in cancer therapeutics

Expanding NK cells

Enhancing NK cell function to eliminate tumors

The role of NK cells in viral therapy

Concluding remarks

References

CH 16. Cytokines in graft-versus-host disease and graft-versus-leukemia

Introduction

Stimuli for cytokine production after hematopoietic stem cell transplantation

Acute versus chronic GVHD

Graft-versus-leukemia effects

Critical cytokines in GVHD pathogenesis

Cytokines involved in Th1 differentiation

Cytokines involved in th2 differentiation

Cytokines involved in Th17/Treg differentiation

Cytokines influencing myeloid development and function

Summary and conclusions

References

CH 17. Chemokines and graft-versus-host disease

Introduction

The study of GVHD: a changing paradigm

Chemokines and the development of acute GVHD

Chemokines and leukocyte trafficking after allogeneic HCT

Chemokines and GVT responses

Advances in the clinical application of chemokine biology during GVHD

Conclusions

Acknowledgments

References

CH 18. Intracellular sensors of immunity and allogeneic hematopoietic stem cell transplantation

Introduction

Intracellular sensors

Metabolic sensors that regulate allogeneic HSCT

Intracellular metabolic changes secondary to immunity

References

CH 19. Proteomics in graft-versus-host disease and graft-versus-leukemia

Definition of biomarkers and pending issues for post-hematopoietic stem cell transplantation clinicians

Current proteomics technologies for biomarker discovery

Major phases of biomarker development

Statistical considerations

aGVHD biomarkers: from the identification of candidates to their validation

Identification and validation of chronic GVHD biomarkers

Identification of GVL and minimal residual disease (MRD) biomarkers

Incorporating GVHD biomarkers in clinical trials

Future research on biomarkers: from diagnosis to therapy

Conclusions

References

CH 20. The endothelium in graft-versus-host disease and graft-versus-leukemia

The endothelium in graft-versus-host disease

Endothelial dysfunction caused by the conditioning regimen

Endothelial dysfunction caused by alloreactivity of donor leukocytes

Antigen presentation and T-cell activation by endothelial cells during GVHD

Neovascularization during GVHD

Inhibition of neovascularization during GVHD

The endothelium in graft-versus-leukemia

Conclusions and perspectives

References

CH 21. Looking toward the future: an individualized approach to allogeneic transplantation

An individualized approach to allogeneic transplantation

The future of GVHD: diagnosis, prognosis

The future of GVHD: treatment

Cellular therapy

Inhibitors of histone deacetylase

Creating platforms for new therapies

Prevention and treatment of relapse

Novel immunotherapeutics

Disease-specific conditioning regimens

Cellular therapy for relapse: natural killer cells

Maintenance therapy following allogeneic transplantation

Improved anti-leukemia effects through T-cell manipulation

Conclusion

References

Index