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In our country, the first apheresis was performed in the late 1960s (by manual technique), and the first cell separator was used in 1979. The number of blood component collections performed from 1994 to 2004 was: 11,170 (total), i.e., 8540 (NBTI), 1180 (IT-MMA), 1050 (BTI of Novi Sad) and 400 (BTI Nis). The number of PBSC harvests during 1996-2004 was 386 for treatment of 272 patients. For treatment of myocardial infarction, "cell-therapy" by autologous stem cells was introduced in 2004 at the MMA. The results of PE treatments performed (7632 sessions) by our group for various immune-mediated and other disorders were generally beneficial, but the effect is not associated with bone marrow remission. TC procedures (total number=1279) resulted in a significant fall in the blood cell counts and hemorheological improvement, as well as the removal and replacement of abnormal red blood cells. Greater standardization of different apheresis protocols is required.

The first cord blood (CB) transplant was performed in 1988 in a patient with Fanconi anemia. The donor was his HLA-identical sister who was known by pre-natal diagnosis to be HLA identical and not affected by the Fanconi mutation. The CB was collected and cryopreserved at birth. The transplant was successful without GvHD and the patient is currently alive and free of disease more than 15 years after transplant, with full hematologic and immunologic donor reconstitution. At the time of the first transplant, little was known about the biologic properties of CB cells and it was thanks to the pioneering work of H. E. Broxmeyer and E. A. Boyse, who studied the progenitor cell content of CB, and of A. D. Auerbach, who realized the pre-natal diagnosis of Fanconi anemia, that this transplant was possible. Since this first transplant, many questions have been answered but others are still open for further research. For example: would a single CB unit contain enough stem cells to permanently engraft children and adults? Would maternal cell contamination in fetal blood engraft and give severe GvHD? What are the immunologic properties of CB cells? How does it interfere with GvHD, GvL and immune reconstitution? Is the immune immaturity of CB lymphocytes able to overcome the HLA barrier and authorize HLA-mismatched transplants? Is it possible to establish CB banks for unrelated and related transplants? What would be the criteria for collection, quality control and cryopreservation?

Hematopoietic stem cells can be collected from the peripheral blood. These hematopoietic stem cells (HSC), or better progenitor cells, are mostly expressed as the percentage of cells than react with CD34 antibodies or that form colonies in semi-solid medium (CFU-GM). Under steady-state conditions the number of HSC is much lower in peripheral blood than in bone marrow. Mobilization with chemotherapy and/or growth factors may lead to a concentration of HSC in the peripheral blood that equals or exceeds the concentration in bone marrow. Transplantation of HSC from the peripheral blood results in faster hematologic recovery than HSC from bone marrow. This decreases the risk of infection and the need for blood-product support. For autologous stem-cell transplantation (SCT), the use of peripheral blood cells has completely replaced the use of bone marrow. For allogeneic SCT, on the other hand, the situation is more complex. Since peripheral blood contains more T-lymphocytes than bone marrow, the use of HSC from the peripheral blood increases the risk of graft-versus-host disease after allogeneic SCT. For patients with goodrisk leukemia, bone marrow is still preferred, but for patients with high-risk disease, peripheral blood SCT has become the therapy of choice.

Allogeneic hematopoietic cell transplantation (HCT) was originally developed as a form of rescue from high-dose chemoradiotherapy, which is given both to eradicate malignancy and provide sufficient immunosuppression for allogeneic engraftment. The first attempts of allogeneic HCT in humans met with little success. However, a better understanding of the complexities of the human leukocyte antigen (HLA) system has allowed selecting compatible sibling donors, and the development of postgrafting immunosuppressive regimens has helped prevent serious graft-versus-host disease, thereby changing the role of allogeneic HCT from a desperate therapeutic maneuver to a curative treatment modality for many patients with malignant hematological diseases. In addition, the establishment of large registries of HLA-typed volunteers has permitted finding suitable unrelated donors for many patients without family donors. Further advances in the immunogenetics of HLA, especially typing by molecular techniques, have improved results after unrelated HCT, which have begun resembling those obtained with HLA-identical sibling grafts, at least in young patients. Important advances have also been made in the prevention and treatment of infectious complications and in other areas of supportive care. Since the late seventies, it has been recognized that allogeneic immunocompetent cells transplanted with the stem cells, or arising from them, mediated therapeutic anti-tumor effects independent of the action of the high-dose therapy, termed graft-versus-tumor (GVT) effects. This has prompted the recent development of non-myeloablative conditioning regimens for allogeneic HCT that have opened the way to include elderly patients and those with comorbid conditions. Remaining challenges include further advances in the prevention and treatment of both severe graft-versus-host disease and infections. Also, progress in adoptive transfer of T cells with relative tumor specificity and disease-targeted therapy with agents such as Imatinib, Rituximab or radiolabeled monoclonal antibodies would make allogeneic HCT even more effective.

During the past 50 yr, intensive studies into the use of hematopoietic cell transplantation (HCT) for therapy of cancer and non-malignant hematologic diseases have changed this treatment modality from one that was thought to be plagued by insurmountable complications to one that is now standard therapy for some diseases. Continued research by transplant teams worldwide is likely to allow continued progress toward developing novel and improved treatment modalities and even wider application of the use of pluripotent hematopoietic stem cells in the treatment of human diseases., (Copyright 2004 Blackwell Munksgaard.)

During the past 50 years, the role of allogeneic hematopoietic cell transplantation (HCT) has changed from a desperate therapeutic maneuver plagued by apparently insurmountable complications to a curative treatment modality for thousands of patients with hematologic diseases. Now, cure rates following human leukocyte antigen (HLA) allogeneic HCT with matched siblings exceed 85% for some otherwise lethal diseases, such as chronic myeloid leukemia, aplastic anemia, or thalassemia. In addition, the recent development of non-myeloablative conditioning and stem cell transplantation has opened the way to include elderly patients with a wide variety of hematologic malignancies. Further progress in adoptive transfer of T cell populations with relative tumor specificity would make the transplant procedure more effective and would extend the use of allogeneic HCT for treatment of non-hematopoietic malignancies.

In the 1950s, the first infusions of hematopoietic stem cells were given as a form of treatment for childhood leukemia. This heralded the beginning of a field that has expanded to include the treatment of immune deficiencies, a variety of leukemias and solid tumors, and then genetic diseases. A number of milestones are highlighted, particularly in regard to the use of alternative sources of hematopoietic stem cells such as unrelated donors, peripheral blood stem cells and umbilical cord stem cells. In addition, newer techniques of using non-myeloablative preparative regimens helped to reduce the toxicity and long-term consequences of hematopoietic stem cell transplant. Many diseases now benefit from the replacement of the marrow stem cells and the provision of a new immune system and improved immune surveillance.

After fifty years of investigations into the use of pluripotent haematopoietic stem-cell transplantation for cancer therapy, this procedure has progressed from one that was thought to be plagued with insurmountable complications to a standard treatment for many haematological malignancies. How have these hurdles been overcome, and how can the therapy be expanded to include patients who are too old or medically infirm to tolerate conventional transplant approaches?

Peripheral blood progenitor cells (PBPCs) have become increasingly popular over the last 15 years as the source of hematopoietic stem cells for transplantation. In the early 1990s, PBPCs replaced bone marrow (BM) as the preferred source of autologous stem cells, and recently the same phenomenon is seen in the allogeneic setting. Under steady-state conditions, the concentration of PBPCs (as defined by CFU-GM and/or CD34+ cells) is very low, and techniques were developed to increase markedly this concentration. Such mobilization techniques include daily injections of filgrastim (G-CSF) or a combination of chemotherapy and growth factors. Leukapheresis procedures allow the collection of large numbers of circulating white blood cells (and PBPCs). One or two leukapheresis procedures are often sufficient to obtain the minimum number of CD34+ cells considered necessary for prompt and consistent engraftment (i.e., 2.5-5.0 x 10(6)/kg). As compared to BM, autologous transplants with PBPCs lead to faster hematologic recovery and have few, if any, disadvantages. In the allogeneic arena, PBPCs also result in faster engraftment, but at a somewhat higher cost of chronic graft-versus-host disease (GvHD). This may be a double-edged sword leading to both increased graft-versus-tumor effects and increased morbidity. The rapid advances in the study of hematopoietic, and even earlier, stem cells will continue to shape the future of PBPC transplantation.

Some malignant and nonmalignant hematological diseases can be cured by the transplantation of allogeneic stem cell. It is thought to be one of the landmarks in the development of modern medicine. Hematopoietic stem cell transplantation has been performed for about one hundred years in the phases of germination, early investigation and development. The great challenge now is how to perfect the technique and to extend the applied areas.

The field of bone marrow transplantation has evolved over a period of 50 years. Reports of beneficial treatment of murine leukemia by irradiation and injection of marrow cells from another mouse stimulated interest in attempting to use these techniques to treat patients with leukemia. The first few bold attempts at human application were generally met with a total lack of success except for a few transplants involving identical twins. Understanding the HLA system led to the ability to select compatible sibling donors. The first successful long-term survivors were reported at the end of the 1960s. During the 1970's patients were given transplants for leukemia after failure of all other treatment. Survivals were poor, but some patients were cured. Transplantation early in the course of the disease resulted in greatly improved survival. During the 1980s improved control of infections, the use of peripheral blood as the source of stem cells, and the ability to select donors other than family members resulted in wide application of hematopoietic cell grafting.

The concise history of BMT development, from experimental studies to clinical practice, is presented. Bone marrow transplantation has been performed in Poland for more than ten years, starting with a few to almost 500 procedures up to 1999. The above was accomplished thanks to successive founding of the 14 active BMT centers throughout Poland, which presently perform from 10 to 130 BMTs per annum (mean 34). About 70% of the above number are autologous BMTs, the remaining are allogeneic BMTs from HLA compatible sibling donors and recently from compatible unrelated donors (URD). During the last few years there is an increasing trend in the number of hematopoietic stem cell transplantations derived from peripheral blood (PBSCT), not only in patients with leukaemias and malignant lymphomas, but also in patients with solid tumors. The BMT results achieved in Poland correspond to results obtained worldwide. In relation to other European countries there are less BMT teams (about 50%) and less BMT procedures (also about 50%) performed per annum (according to EBMT data calculated per 10 million inhabitants). Thanks to the financial support of the Polish Ministry of Health more and more patients are qualified for high dose chemotherapy, increasing their chances for long term disease free survival and, eventually, for cure.

Cells normally present in the circulation are capable of providing sustained haematopoietic function in a manner similar to cells normally present in the bone marrow, when transplanted to an autologous or allogeneic recipient. The function of these circulating cells is not known, but they may serve as a reservoir of haematopoietic stem cells which can migrate via the blood stream to sites of need when called upon, thereby providing a protective role. In the past, these cells were collected from the blood during steady-state marrow function to serve as both autologous and allogeneic graft products for transplantation. While this application has since been abandoned in favour of mobilized blood stem-cell transplantation, laboratory investigation of non-mobilized circulating stem cells will be needed if a full understanding of their purpose and function is to be learned.

We review the development of the hematopoietic system, focusing on the transition from hematopoietic stem cells (HSCs) to T cells. This includes the isolation of HSCs, and recent progress in understanding their ontogeny, homing properties, and differentiation. HSC transplantation is reviewed, including the kinetics of reconstitution, engraftment across histocompatibility barriers, the facilitation of allogeneic engraftment, and the mechanisms of graft rejection. We describe progress in understanding T-cell development in the bone marrow and thymus as well as the establishment of lymph nodes. Finally, the role of bcl-2 in regulating homeostasis in the hematopoietic system is discussed.

The history of clinical marrow transplantation since 1968 is reviewed with an emphasis on immunological and immunogenetic aspects. The events leading to the creation of an international network of volunteer donor registries and the implementation of unrelated allogeneic marrow transplantation as a routine procedure are discussed. Current major issues which need to be resolved are addressed in order to set the stage for the topics covered in this volume of Immunological Reviews.

Peripheral blood stem cells (PBSC) are rapidly becoming the primary rescue modality for autologous transplantation and are now actively being investigated in the allogeneic transplant setting. Many investigators and clinical researchers believe that PBSC are likely to replace bone marrow stem cells entirely, for use in clinical transplantation in the not too distant future (1). In order to better understand the rapidly changing developments in this field, it would be helpful to understand the historical development of this technology. The purpose of this article is to build for the reader a strong historical foundation with the intent to integrate the history of peripheral blood stem cells with their subsequent isolation, mobilization, collection, and clinical applications.

Our growing physiological understanding of hematopoietic progenitor cells has led to the clinical use of circulating progenitor cells, including stem cells, for either reconstitution of hematopoietic function, up to the transduction of functional genes into a self-renewing cell system. In the following, an attempt has been made to recollect the major steps in the evolution of clinical blood stem transplantation, from the morphological description of small lymphocytes circulating in the blood up to somatic gene therapy covering a time period of 87 years.

Attempted human allogeneic marrow transplants in the 1950s and 60s were largely unsuccessful. In the past two decades the probability of success has improved steadily depending on the type and stage of disease. Cure rates range from about 90% for nonmalignant diseases transplanted early to 15% for patients with advanced leukemia. Most marrow transplants have involved an HLA matched sibling donor but, more recently, through the National Marrow Donor Program, a matched unrelated volunteer marrow donor can be found for many patients without a family donor. Current research involves new preparative regimens for elimination of malignant cells, better prevention of graft-versus-host disease, and the use of hematopoietic growth factors and cytokines. Autologous transplants, which use the patient's own marrow, are increasing. The hematopoietic stem cell, which is responsible for marrow regeneration after a transplant, has been isolated and characterized. Stem cells for transplantation can now be obtained from the peripheral blood after mobilization of these cells by chemotherapy or hematopoietic growth factors. A variety of technological advances makes it possible to perform transplants with less time in the hospital and a corresponding saving in cost.