Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with hematologic malignancies and other blood disorders. In addition to delivering effective anti-cancer treatment, the therapeutic potential of allogeneic HSCT relies on graft-versus-tumor (GVT) effects, which eradicate residual malignant cells via immunologic mechanisms. Unfortunately, GVT effects are closely associated with the development of graft-versus-host disease (GVHD). GVHD and malignant relapse are the two primary contributors to mortality, which remains unacceptably high. Standard therapy for GVHD is often therapeutically sub-optimal and predisposes to opportunistic infections and relapse of the underlying disease. Thus, the development of novel strategies that reduce GVHD and enhance survival after allogeneic HSCT remains the most significant challenge facing physician-scientists and our patients. The pathophysiology of GVHD is complex and fundamentally depends upon interactions between donor T cells and host antigen presenting cells. Experimental and clinical data support the hypothesis that cytokine dysregulation during GVHD occurs in three distinct phases including: 1) the effects of conditioning regimens on host tissues, 2) activation of donor T cells by host antigen presenting cells and 3) the generation of cellular and inflammatory effectors. While simplistic, this 3-step hypothesis uncovers opportunities to regulate this disease process. We have recently explored the role of cyclin dependent kinase 5 (Cdk5) in immune cells. Cdk5 is a ubiquitously expressed serine-threonine kinase that is predominantly active in post-mitotic neurons where the expression of its obligate partner proteins (p35 and p39) is most abundant. Cdk5 activity is essential in various neuronal processes, and as such, current paradigms suggest that Cdk5 function is largely restricted to the CNS. Activation of the Cdk5/p35 complex is however associated with inflammatory disorders, but the contribution of Cdk5 activity to lymphocyte biology has not been fully appreciated. Recently, our group was the first to implicate a role for Cdk5 in lymphocyte activation by 1) developing a new chimeric mouse model in which hematopoietic stem cells from Cdk5 deficient (Cdk5-/-) embryos are used to reconstitute lethally irradiated adult mouse recipients (CDK5-/-C), 2) showing the rapid induction of both Cdk5 and its obligate partner p35 during T cell activation, 3) revealing defects in activation and migration of Cdk5-/- T cells from adult chimeric CDK5-/-C mice;and 4) demonstrating a resistance to the induction of experimental autoimmune encephalomyelitis in CDK5-/-C mice immunized with a MOG peptide. Exciting preliminary data strongly suggest a role for Cdk5 in modulating GVHD severity as well. However, the mechanisms for this protective effect must be further defined. These findings are significant because they identify potential targets for novel cellular therapeutic strategies that are non-cross reactive with standard immuno-suppressive approaches and therefore have the potential to reduce GVHD severity while maintaining immune reconstitution and GVT effects.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with benign and malignant blood disorders. Graft-versus-host disease (GVHD) and malignant relapse are the two primary contributors to mortality following allogeneic HSCT. Standard therapy for GVHD is therapeutically sub-optimal, thus the development of novel strategies that reduce GVHD, enhance immune engraftment and reconstitution and improve survival after allogeneic HSCT remains the most significant challenge facing physician-scientists and our patients. Our laboratory team has recently uncovered a heretofore unknown role for the protein called cyclin dependent kinase 5 (Cdk5) in the activation of immune cells that contribute to GVHD. Thus, a better understanding of the role of Cdk5 in the development GVHD may result in generation of new strategies to prevent or treat this process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111682-02
Application #
8722595
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Welniak, Lisbeth A
Project Start
2013-08-19
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$388,325
Indirect Cost
$73,505
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106