History:
After completing his studies, Dr. Jiga returned to Romania and immediately the idea of a new experimental laboratory was fostered, that would begin something practically unexplored yet in this country, namely the development of a local universitary research infrastructure having as main purpose the study of dendritic cells, the most potent immune cells, and how they could be artificially engineered to become both suppressive or specific immune activators to inhibit and overcome solid tumor growth.
Having one of those concepts as guide, Dr. Jiga successfully applied for a Reintegration Fellowship sponsored by NATO and the Security Through Science Program. With the consistent help given by this initial founding, the dream become a reality and in August 2005, through combined efforts of Prof. Virgil Paunescu (Chief of the Immunology Department, Director of the Center of Immunophisiology and Biotechnologies, Timisoara) and Prof. Mihai Ionac (Chief of the Microsurgery Division, and Director of the Pius Branzeu Center, Timisoara) our laboratory was founded. Some of the basic equipment was kindly donated by the Department of Immunology and the laboratory rooms were provided by Prof. Ionac, at the Pius Branzeu Center for Laparoscopic Surgery and Microsurgery. After 4 years, we are proud of our intensive activity, as coordinators of 5 major national and international research projects, in a newly renovated laboratory. We have grown to become a solid team of researchers, constantly looking forward, towards new challenges in our field of research.
The main purpose of our laboratory is to research and develop new cell-based therapies to either specifically suppress or activate the immune system, as novel therapeutic ways to overcome immunological rejection in organ transplantation or to stop and annihilate tumor cell growth. In the center of this concept, dendritic cells play the main role.
Dendritic cells and transplantation tolerance
Over the last decade, these cells have proved their unique qualities as principal regulators of the both innate and acquired immune response, being at the same time, key players during immune activation after organ transplantation. Today, for a transplanted organ to survive, it needs permanent/ constant pharmacological immunosuppression, administered to the patient each day for the rest of his life. Such therapy suppresses on one side, the entire immune response and thereby any reaction against the transplanted graft, but on the other side, it exposes the organ recipients to opportunistic infections, cancer or chronic rejection, all being threatening complications which darken the a-la-long prognosis and life expectancy of these patients. The ideal solution to these ever evolving problems is the permanent suppression of only that part of the immune reaction, specific for the donor antigens. Thus, all the possible complications related to pharmacological immunosuppression could be eliminated while, preserving indefinite survival of the transplanted organ. This phenomenon is called immunological tolerance. Being known that dendritic cells are the main “actors” on the immune response “scene”, in an effort to induce transplantation tolerance, it was found that their artificial manipulation by pharmacological or genetic engineering, can lead to their transformation into suppressive or tolerogenic cells, thus being able to specifically suppress the immune response against transplanted organ allografts. Nevertheless, although, experimental results are promising, generation of tolerogenic dendritic cells for clinical application represents today the “holy grail” in transplantation immunobiology, and such a therapy needs yet to be discovered. One of the main goals in our laboratory is, to study the behavior of in-vitro generated dendritic cells and possibilities of manipulating them to suppress allospecific T- cell activation in-vitro for inhibition of allograft rejection in organ transplantation.
Dendritic cells and cancer immunotherapy
Dendritic cells (DCs) are considered today the most potent type of antigen presenting cells and are vital for inducing specific immune responses through activation and clonal expansion of T-lymphocytes. This unique property has prompted the development of new therapeutic approaches by using these cells as cancer vaccines. Either in-vitro generated or directly isolated pulsed with certain tumor antigens (tumor lysate, tumor-associated-antigens, heat shock proteins, etc) in-vitro and administered as a cellular vaccine, have been found to induce protective and therapeutic anti-tumor immunity in different experimental models.
Although, clinical evaluation of DC immunotherapy, for the treatment of certain malignancies such as melanoma, prostate cancer or lymphoma, is still in its earliest phases, the results obtained until now are very promising. DC immunotherapy consists of generating dendritic cells in-vitro under certain conditions (growth factors – GM-CSF, IL-4, etc) from either circulating blood monocytes or bone marrow cells taken from the patient. Immature DCs are then exposed to proteins isolated in different ways from the same patient cancer cells and then co-cultured with autologous T-lymphocytes. After this culture period, specific cytotoxic anti-tumor CD8 T-cells are isolated, purified and multiplied. As a last step, these tumor-specific killer cells will be infused into the patient when sufficient numbers have been obtained.
Although big progresses had been made, in both defining the mechanisms responsible for anti-tumor response and also the role of DCs as potential therapy to overcome malignant disease, no conclusions regarding the efficacy of such vaccines can be yet made from the brief reports published in peer-reviewed medical literature. Problems such as the right type of tumor antigen, tumor-antigen specificity, DC-loading strategies, vaccine doses, administering schedules or administration route still remain to be clarified in the near future.
Developing new protocols for in-vitro generation and characterization of clinical-grade dendritic cells to be used as anti-tumor cell-based vaccines represents one of our laboratory main research aims.
Endothelial progenitor cells and introduction of angiogenesis
Critical limb ischemia represents today a major health problem. Worldwide, this disease is generating a general mortality rate of more than 20% and represents the principal major amputation cause in more than 38% of the patients in the first 3 years after the initial diagnosis. All these dreadful results are due to the lack of an actual effective treatment for the advanced stages of the disease, where amputation remains the only choice to alleviate unbearable symptoms or to save the patients life. Numerous actual studies bring conclusive clinical and experimental arguments regarding the role of the pluripotent CD34+ cells in the vascular reconstruction of the ischemically injured tissues. The capacity of these cells to induce therapeutical neoangiogenesis relay mainly upon the bone marrow endothelial progenitors that are crucial for the induction of local vasculogenesis. Moreover, concomitant administration of CD34+ cells with prostaglandin-like substances (Ex. Illoprost) that act to dilate the precapillary remnant vessels in the ischemic tissue may further improve to overall revascularization effect of such therapies with gangrene limitation. The use of autologous CD34+ cells in the treatment of critical limb ischemia in the laboratory rat and to study the effect of local administration of autologous CD34+ cells with or without the presence of vasodilating prostaglandines. The results obtained in this study represent the fundamental infrastructure for clinical implementation of such therapies in the near future.
The beginnings:
It all started in 2002, when Dr. Lucian Jiga, took a PhD fellowship at the Institute for Immunology of the Ruprecht-Karls University in Heidelberg, Germany. There, both he and his wife (Dr. Janina Jiga) worked in the Department of Transplantation Immunology under the direct guidance of Prof. Terness, discovering the fascinating world of the immune response and how this phenomenon could be eventually used as a therapeutic strategy to overcome acute rejection in organ transplantation or tumor growth in cancer disease.
Their research produced very interesting results, especially in the field of transplantation immunobiology, where they produced, after in-vitro manipulation, a new suppressive dendritic cell which is able to inhibit the specific alloimmune response, thus allowing prolonged allograft survival in an experimental model of heart transplantation.
Our purpose:
