Chaim Roifman, MD, FRCP, FCACB
The Hospital for Sick Children
Immunology & Allergy
University of Toronto
Paediatrics, Medicine and Immunology
The Hospital for Sick Children
Donald and Audrey Campbell Chair in Immunology
- Lymphoid Malignancy
- Gene Therapy
- Animal Models
- Drug Development
- Signal Transduction
Molecular basis of immunodeficiency and lymphoid malignancy.
The focus of research in my laboratory includes the identification and functional characterization of novel signal transduction pathways in normal lymphoid tissues and their role in immunodeficiency and leukemia/lymphoma. This work has resulted in the cloning of a T-cell specific tyrosine phosphatase, "Lyp", and protein tyrosine kinase, "Jak2". We have previously shown that Jak2 appears to play a critical role in leukemogenesis. We are developing Jak2 knock-out mice to further the understanding of its function. We are also developing potent, specific and non-toxic inhibitors of Jak2 as potential chemotherapy agents.
It has been demonstrated that mutations in the ZAP70 kinase gene eliminate immune function severely. Consequently, T lymphocytes lacking functional ZAP70 kinase do not respond satisfactorily to antigenic stimulation. This phenomenon due to a mutation in ZAP70, has been observed in patients with a form of hereditary (autosomal recessive) immunodeficiency disease. Treatment of these patients (as well as others with ZAP70 deficiencies) by gene replacement to reconstitute ZAP70 may prove to be an effective means of therapy.
We have identified a novel immunodeficiency syndrome which overlaps autoimmunity and profound cellular deficiency. A mutation in the interleukin-2 receptor (IL-2Ra) was found to cure this syndrome, thus enhancing our knowledge and understanding of IL-2Ra function. Analysis of the regulatory elements of this gene as well as those of the ZAP70 gene and the creation of animal models of immunodeficiency will provide the basis for future gene therapy.
We have demonstrated that the Eph family of receptor kinases and their ligands the ephrins play an important role in T lymphocyte biology, regulating T cell activation and migration. Eph receptor expression has been shown to play an important role in cancer spread and may be critical in the spread of T cell lymphomas and leukaemias.
Other Laboratory Findings Include:
- Discovery of a novel defect in CD3ƒÔ gene involved in Severe Combined Immunodeficiency (2003)
- Evidence that Eph B6 is an active signaling receptor in lymphocytes (2002)
- Description of Il-7RƒÑ Severe Combined Immunodeficiency (2000)
- Analysis of the outcome of a bone marrow transplant protocol using matched unrelated donors, bone marrow ablation and GVHD prophylaxis(2000)
- Mechanism of inducing immunodeficiency in PNP deficiency via PNP -/- knock out mice created at HSC (2000)
- Discovery of Roifman¡¦s syndrome: a novel syndrome of CID, autoimmunity and spondylometapheseal displasia (1999)
Roifman CM: CD3 delta immunodeficiency. Current Opinion in Allergy and Clinical Immunology 2004: 4: pp 1-6.
Dror Y, Grunebaum E, Hitzler J, Narendran A, Edwards V, Freedman MH, Roifman CM: Purine nucleoside phosphorylase deficiency associated with a dysplastic marrow morphology. Pediatric Research 2004: 55 #3: pp 1-6.
Triassi M, Roifman C: Common gamma chain mutation R222C causes atypical severe combined immunodeficiency (SCID) phenotype. Journal of Allergy and Clinical Immunology 2003: 111: pp S232.
Grunberger T, Sharfe N, Rounova O, Demin P, Dadi H, Freywald A, Cimpean L, Toro A, Estrov Z, Roifman C: Inhibition of Acute lymphoblastic and myeloid leukemias by a novel kinase inhibitor. Blood 2003: 102: pp 4153-4158.
Sharfe N, Freywald A, Toro A, Roifman C: Ephrin A1 induces stimulation in c-Cbl Phosphorylation and EphA receptor downregulation in T cells. The Journal of Immunology 2003: 170: pp 6024-32.
Harjit D, Simon A, Roifman C: CD3 delta deficiency in humans arrests maturation of alpha beta and gamma delta T cell lineages leading to severe combined immunodeficiency. New England Journal of Medicine 2003: 349: pp 1821-8.
Freywald A, Sharfe N, Rashotte C, Grunberger T, Roifman CM: The EphB6 receptor inhibits JNK activation in T lymphocytes and modulates T cell receptor mediated responses. Journal of Biological Chemistry 2003: 278: pp 10150-6.