Immunology and, more specifically, mechanisms of immune tolerance have long been a major focus of biomedical research. For decades, scientists have puzzled over the intricate molecular pathways and mechanisms of cellular interactions involved in the immune response. It was recognized early on that their manipulation could significantly aid the treatment of numerous diseases. Though many benchmarks have been reached, a number of proposed modes of immunotherapy remain undiscovered.
Many target molecules have such broad specificity and functionality that a multifaceted approach must be adopted to truly understand the pathways involved. Therefore, institutions have formed interdepartmental partnerships, in addition to close collaborations with facilities across the globe, to best utilize resources and gather as much detailed information as possible.
Research teams combine the skills of cell biologists, molecular biologists, and biochemists to study the many components of the immune response. A lot of these teams use various organ or cell-specific experimental models for their particular area of research.
Collaborations with teaching hospitals and transplantation centers have provided the lucky few with the opportunity to study disease-specific mechanisms at a cellular or molecular level using primary cell types. These collaborations often provide the facilities and opportunities to work with clinical research teams so that research can be integrated with clinical trials to gather essential patient data.
However, such ground-breaking research has not been without its difficulties and limitations. The field is constantly changing—new discoveries lead to more questions, exposing further areas for study. Moreover, interpatient variability within a disease type or particular response further dictates the need for the development of a more personalized approach to therapeutic intervention. These scientific leaps in molecular medicine require innovation. To truly drive such discovery, a consistent input of new technology is required, but this also involves substantial investment. Thus new forms of funding and support are constantly being sought.
A number of institutions have worked not only to form collaborations with their peers but have come to realize the mutual benefit of industry partnerships. This is not novel in itself; many academic laboratories have received industry/pharma backing in return for material or cell supply, however, the approach has evolved substantially.
Combining the wealth of knowledge, understanding, and practical know-how gathered over many years of research with the technical and application expertise of industry scientists can enable a more informed approach to biomedical research. This can benefit not only the industry as a whole, but significantly further biomedical research, providing innovative new methods for the identification of highly relevant therapeutic targets. It can also allow the commercialization of these discoveries to fund further research. One center that has embraced this approach is the Research in Immune Tolerance and Transplantation (RITT) center in Toronto.
Centers of Excellence
The RITT program is part of a new $12-million initiative that aims to fully understand the biology of transplant rejection in order to develop treatments to prevent it. The program is part of the research arm of the Multi Organ Transplant Program, which carries out 430 solid organ transplants a year. The center spans numerous scientific disciplines and clinical departments and is fully committed to education, research, and patient care, combining the expertise of surgical, clinical, research, and, more recently, industry teams.
This allows the center to provide real bench-to-bedside medicine. Working under one administrative system significantly improves the speed of specialized patient care and the economic viability of the facility. There are no duplicate systems and patient treatment, testing, clinical trials, and associated research are all under one roof.
The RITT is a respected center of biomedical research with substantial funding to support its surgical and research programs. It is thus heavily involved with developing new transplantation and research protocols, such as the new encapsulated islet transplant—the first transplantation of specially coated insulin-producing islet cells into a patient with type 1 diabetes. With 31 transplantation scientists and 337 active protocols, this extensive team has already contributed greatly to the scientific community and published an average of 111 papers per year.
At the Bench
The center is primarily made up of five research teams whose combined focus is to study the mechanisms of immune tolerance and organ rejection in order to develop and test concepts and proteins for immunomodulatory therapeutics. The teams approach this task from numerous angles, all with a common goal to identify the genes/proteins involved. The teams have a series of progressive in vitro and in vivo studies investigating:
• The role of Fibrinogen-like protein 2 (fgl2/Fibroleukin) in the regulation of transplantation immunity. More specifically, its immunomodulatory effects on T cells and bone-derived dentritic cell maturation and the regulation of immunity by purified and recombinant, soluble fgl2.
• The immunosuppressive role of the Ig Supergene family member CD200, using immunization studies to understand its regulatory effects on pro-inflammatory conditions, like arthritis and allograft rejection.
• The mechanisms that regulate the function and homeostasis of double negative regulatory T cells, their role in peripheral tolerance, and how they work in an antigen-specific manner to suppress the immune response.
• The utilization of transtracheal delivery for adenoviral-mediated gene transfection and the effects of transplant immunosupression on allograft function and survival.
• Disease-specific (hepatic) transcription profiles using microarray technology—a highly sensitive, high-throughput technique to determine the mRNA levels for thousands of genes involved in the pathogenesis of liver disease.
Following the identification and study of specific genes and protein groups, potential candidates are passed on to the RITT Industrial BioDevelopment Laboratory (IBDL; www.ibdl.ca) for further determination, characterization, and isolation. It is here that industry partnerships play a crucial role and development and testing takes place using a variety of novel instrumentation and methodologies.
Set among a hive of scientific activity, this “industrial incubator” has attracted many companies and encouraged further government funding and approval. With a selection of small biotech companies residing adjacent to the center, additional funds are generated to really drive this research.
The RITT center received an infrastructure award from the Canada Foundation for Innovation worth $20 million and has been designated a premiere Canadian site for beta-testing new bioanalytical technology. This has helped RITT find funding for equipment for the general research labs, spanning 4,000 square feet; the IBDL facility, spanning a full 1,800 square feet; the state-of-the-art imaging facility; and the cell-sorting facility.
The IBDL alone is made up of numerous laboratories, including labs for upstream and downstream processing, microbiology, cell processing, instrumentation, and wet chemistry, in addition to cold and warm rooms. To equip both the general lab and the IBDL facilities, collaborations with vendors, such as Thermo Fisher Scientific (www.thermofisher.com), have been formed and a multitude of instrumentation has been installed.
From Thermo Fisher the list includes biological safety cabinets, lamina-flow stations, CO2 incubators, orbital shakers, ultra-low temperature freezers, a mass spectrometer, HPLCs, UV/visible spectrophotometers, microplate instrumentation, and a KingFisher magnetic particle processor for protein purification. With over $1 million of equipment, this has been one of the IBDL’s biggest investments in a single supplier.
However, it is acknowledged that it is not just the hardware that can be of great benefit to these facilities, but the technical and application expertise of the scientists involved with their development. Thus, it was proposed that industry partners should be closely involved with the educational component of the RITT center. As a result, vendors are involved with student training, industrial biotechnology seminars, and the sponsorship of training facilities and workshops—all providing long-term benefits to the center. Workshops cover subjects such as ultrafiltration, ELISA development, and mass spectrometry applications, to name just a few.
There has also been the opportunity to support the RITT’s objectives by funding a post-doctoral research scientist for two years. The Bioanalytical Post-doctoral Fellow works on projects of mutual interest, in particular the development of new biomarkers, specifically concentrating on the areas of assay development and biomolecule purification.
Relationships for the Long-term
For RITT, the industry collaborations have proved to be extremely beneficial and an exciting opportunity for many, motivating research teams and stimulating novel ideas for the development and optimization of experimental procedures. Utilizing investment to capitalize on new discoveries, the RITT center aims to generate $200 million in the next five years to filter back into the research.
Maintaining a balance between the capitalization of innovative biotechnology development and the real benefits this can bring to transplant medicine is, without a doubt, essential. However, it is widely acknowledged that such collaborations have the ability to catapult this area of research forward, bridging the once rather large gap between industry and academia, and allowing the development of exciting new therapeutics for the future.