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Immunology and Allergy
Immunology and Allergy

Research activities

Molecular and genetic basis of Primary Immunodeficiency

  • Chaim Roifman, MD
  • Amos Cohen, PhD
  • Harjit Dadi, PhD
  • Andrea Newell

Often in research, identification of a mutation provides a method of detecting a disease and its carriers, while providing the basis for gene therapy. From investigating novel cases of combined immunodeficiency, new immunodeficiency syndromes such as ZAP-70 kinase deficiency were discovered. These discoveries aided in the treatment of such patients, while furthermore providing a means of diagnosis for future patients.

Signal transduction

  • Chaim Roifman, MD
  • Nigel Sharfe, PhD

The research has revealed the various steps in the mechanism of activating lymphocytes which has in turn aided in the understanding of many significant inherited immunodeficiencies that are based on abnormal lymphocyte activity. With continued work on identifying the mechanism of signal transduction, the groundwork for new concepts in designing specific and nontoxic therapies is provided.

Molecular basis of vulnerability to infections and lymphoid malignancies

  • Chaim Roifman, MD

Molecular studies in the development of infections and lymphoid malignancies have generated strategies to eliminate leukemia cells in SCID mice, via preventing the expression of a key component which has been found to be a vital element in leukemia cell production. This lymphoid growth activator is called Jak-2 PTK, and has been cloned, sequenced and characterized by Dr. Roifman's group. Hence, such research for susceptive molecular elements and their inhibitors represent ideal candidates as chemotherapeutic agents in humans.

IVIG clinical trials

  • Brenda Reid, RN
  • Chaim Roifman, MD

The IVIG program at The Hospital for Sick Children evolved out of Dr. Roifman’s research studies into the efficacy of intravenously administered gammaglobulin in the 1980s. These studies showed that by administering higher doses of gammaglobulin intravenously, and bringing the pre infusion IgG level into the normal range, the progression of chronic lung disease could be prevented in the majority of patients. These studies, along with the successful effect on IVIG on dermatomyositis, juvenile rheumatoid arthritis, and peripheral neuropathy, have made IVIG infusions the main form of therapy for antibody deficient patients, and accredits the IVIG program at SickKids as the first centre to treat patients with high doses of intravenous gamma globulin. With a large group of patients with a relatively uncommon disease, the Immunology team at SickKids has been given the opportunity to carry out many clinical research studies on these patients and gammaglobulin treatment. In the last several years, there have been publications on CT scan findings in hypogammaglobulinemia and the long-term outcome of these patients. As well, we have been Primary Investigators on several North American industry funded gammaglobulin studies including IGIV-C Chromatography study funded by Bayer Corporation (contributed the largest number of patients to this study from one site), Aventis Behring CE 1200 Subcutaneous Gammaglobulin Study, and Bayer Corporation Rapid Infusion Study.

Stem Cell therapy

  • Chaim Roifman, MD
  • Adelle Atkinson, MD
  • Eyal Grunebaum, MD

In the past, stem cell therapy primarily consisted of Bone marrow transplantation whereby a patient received stem cells via the insertion of the bone marrow, or cells derived from bone marrow through a bone marrow aspirate. However with suitable bone marrow donors being rarely available, innovative options had to be explored. In recent years, improved understanding of immune system development, the availability of drugs that affect immune function, and better methods for specifically selecting cells responsible for immune reconstitution, has aided medicine in locating other sources of hematopoietic stem cells. Cord blood was found to be particularly rich in cells capable of immune development, and cord blood registries are being created similar to bone marrow registries. At the Hospital for Sick Children, cord blood is particularly attractive, as there is reduced frequency of adverse reactions in the recipient. Furthermore, many immunodeficient patients that are in need for immune reconstitution are infants. Thus the relative small amount of cord blood that is available is usually is not a limitation. Another option that is now more commonly explored, and has also been successful in a few cases at The Hospital for Sick Children, is the use of stem cells derived from peripheral blood. There are very few hematopoietic stem cells in the peripheral blood, however a significant amount of such cells can be mobilized from the bone marrow with the aid of different pharmacological agents. This allows collection of large amounts of stem cells with relatively less discomfort to the donor compared to bone marrow aspirate. Although the peripheral blood contains also many unwanted cells, including cells that can aggravate graft versus host disease, advances in the purification methods of cells has allowed the safe use of such procedures. In the future we estimate that the availability of different sources of stem cells will enable transplantation in a more patients than was in the past.

Gene therapy

  • Eyal Grunebaum, MD

Many human illnesses, such as cystic fibrosis, some forms of cancer and the majority of the primary immune deficiencies are caused by defects at single genes. Therefore, replacement with an external functional gene has been long sought as a therapeutic option. Among these diseases, severe combined immune deficiency (SCID) is one of the most suitable to pursue, due to the discovery of an abnormal gene that is important in the functioning of the immune system, and the relative easy access to blood components that mediate the immune response. Bone marrow transplantation is currently the only cure for SCID patients. Unfortunately suitable donors are available in less than a third of the cases, and the procedure itself is associated with many side effects. With the goal of providing an alternative treatment to these patients, research conducted by Dr. Eyal Grunebaum has overcome many obstacles. These include finding an appropriate vehicle or vector to carry the gene, delivery of the gene to the specific cells, and ensurance of a long lasting, stable functioning gene.

Novel Anti-Leukemia Drugs

  • Chaim Roifman, MD
  • Peter Demin, PhD
  • Olga Rounova, PhD
  • Tom Grunberger, PhD

One of the main goals and directions in this research facility is the conversion of original discoveries made over a number of years, to its application towards novel therapies in cancer treatment. The therapy of hematopoietic cancers is typically accomplished by the administration of chemotherapy over a course of several weeks to months, often in combination with intensive radiotherapy. These treatments non-selectively target almost all cells, harmfully affecting a variety of physical functions as diverse as bone marrow, the immune system, the digestive tract, and the central nervous system. These therapeutic applications are also frequently ineffective at eradicating aggressive cancers. In recent years, synthetic inhibitors of specific bodily proteins have made a rapid transition from basic research to therapeutic application. Designed to modulate a particular target, these compounds represent a major clinical advancement in the treatment of such cancers. Synthetic compounds are considered acceptable for clinical application in haematopoietic cancer, providing they are stable, and do not possess the non-specific destructive nature that is visible with chemotherapy and radiotherapy. At SickKids a number of novel compounds that were believed to possess this ability to halt the activity of haematopoietic cell malignancies, were systematically synthesized by Peter Demin and Olga Rounova. Their ability to block the growth and multiplication of leukemic cells, while permitting the growth of normal cells to proceed unaffected has been successfully studied both in vitro and in mice by Tom Grunberger with promising results, while positive findings were similarly revealed in separate models that are utilized to assess specifically physical toxicity and the termination of cancer cell growth.

Lymphoma Therapy

  • Chaim Roifman, MD
  • Peter Demin, PhD
  • Olga Rounova, PhD
  • Tom Grunberger, PhD

Recent reasearch has proven that many children with lymphoma also have a primary immunodeficiency. This discovery will likely lead to a change in practice from standard chemotherapy only, to a combination treatment that includes bone marrow transplantation. It is hoped that this new treatment program will improve survival rates for children with this condidtion.

National Repository and database of PID

  • Chaim Roifman MD
  • Linda Pires  HonBSc

Congenital forms of immunodeficiency have been known for more that four decades and were considered extremely rare. Initially, only the most extreme and profound immunodeficiency cases, such as severe combined immunodeficiency occurring early in childhood, were carefully classified and received scientific and medical attention. Subsequently many more types of T cell and B cell immunodeficiencies have been identified, including the genetic abnormalities that underlie them. Linked to an international network of registries, this centralized national database for immunodeficiency will aid in the awareness of these escalating primary immune deficiencies among specialists, general practitioners, patients, and the public. Through its sheer volume this database will facilitate phenotypic recognition, demographic studies and evidence-based clinical trials on this minute population of PIDs. Correspondingly the registry will be critical in tracing and evaluating various modes of therapy, diagnosis, and adverse reactions, in areas such as the use of immunoglobulin, via its incorporation of clinical manifestations, laboratory values, and treatments for PIDs. It is through this Repository that the process of clinical examination and diagnosis can be ascertained swiftly, early on in life, to eleviate the downfalls of a delayed diagnosis in patients, while improving the current clinical protocols in this area of medicine.