[Frontiers in Bioscience E4, 721-733, January 1, 2012]

T-cell phosphokinome as a fingerprint of effective graft versus leukemia

Manu O. Platt1, Melissa L. Kemp1

1Wallace H. Coulter Department of Biomedical Engineering and Institute for Bioengineering and Biosciences, Georgia Institute of Technology and Emory University, Atlanta, GA 30332

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Complications of distinguishing GvHD from GvL responses
3.1. Antigen specificity
3.2. Immune cell involvement
4. Phosphokinome Analysis: Cues
4.1. Conditioning regimen and patient state
4.2. Antigen initiation of cascades
5. Phosphokinome Analysis: Signals
5.1. T cell receptor signaling
5.2. Interferon and interleukin: signaling through JAK/STAT
5.3. Cytotoxic pathway signaling
5.3.1. TNF/TNFR
5.3.2. FasL/Fas
5.4. Signaling measurement methodologies
6. Phosphokinome Analysis: Responses
6.1. Cytokine profiling
6.2. Immune cell behaviors
6.3. Pre-clinical and clinical responses
7. Benefits and challenges of phosphokinome analyses
8. Acknowledgements
9. References

1. ABSTRACT

Bone marrow and hematopoietic stem cell transplants are given to leukemia patients after chemotherapy and ablative preconditioning, but a significant number will suffer from graft versus host disease (GvHD), where donor immune cells attack recipient tissues. Some graft versus leukemia (GvL) activity protects from leukemia relapse, but determining this balance requires multi-factorial consideration. Genetic and cytokine studies have attempted to improve patient outcome predictions, but there is still far to go. Here, we describe important considerations of the phosphokinome as a fingerprint for predicting GvHD and GvL with partial least squares regression (PLSR) multivariate analysis. Distinguishing factors of GvHD and GvL will first be highlighted to appropriately measure T cell responses to cues that stimulate opposite, orthogonal, and overlapping responses. We will also discuss important kinase signaling cascades predicting cellular responses of cytokine expression, proliferation, and death linked with GvHD or GvL. Higher throughput methods to characterize these signals and different model systems will be discussed, along with benefits and challenges of using the T cell phosphokinome as a fingerprint to predict GvHD and GvL.