History of graft-versus-host disease.

Nuclear warfare at the end of World War II inspired Dick W. van Bekkum to study total-body irradiation (TBI) in animal models. After high-dose TBI, mice died from "primary disease" or bone marrow (BM) aplasia. Intravenous administration of allogeneic BM cells delayed mortality but did not prevent it. Initially the delayed deaths were said to be caused by "secondary disease," which was later renamed graft-versus-host disease (GvHD). GvHD is caused by donor T lymphocytes that destroy recipient cells in skin, intestinal mucosa, bile ducts, and lymph nodes. GvHD is opposed by host-versus-graft disease (HvGD), in which host T lymphocytes destroy the administered allogeneic BM cells, including the administered T lymphocytes of the BM donor. In 1960, van Bekkum became the director of the Radiobiological Institute of the Dutch Organization for Applied Scientific Research TNO, Rijswijk, The Netherlands, where he built a multidisciplinary team that defined the variables controlling the outcome of a BM transplant. The team published their early results in the Journal of Experimental Hematology [1981;9:904-916 and 1956;4:482-488]. Later, protocols were established for BM transplantation (BMT) in patients with severe combined immunodeficiency disease, leukemia, lymphoma, and other diseases of the hematopoietic system. This review honors the scientific contributions made by Dick van Bekkum and his team in defining the four dominant variables for improving the therapeutic ratio of allogeneic BMT and in fostering the international collaboration necessary to translate this knowledge into current clinical practice.

Enfermedad injerto versus huésped / Graft versus host disease

La enfermedad injerto versus huésped (EIVH) es una entidad de frecuente presentación en las personas que son intervenidas con alotrasplantes. Es inducida y mantenida por las células inmunocompetentes del injerto, que atacan los tejidos del huésped; especialmente los epitelios. El diagnóstico de la EIVH es clínico, apoyado en la histopatología, pero esta, por sí misma, no permite diagnosticar la entidad. La primera línea de tratamiento de la EIVH continúan siendo los esteroides sistémicos y ante refractariedad para estos, aparecen nuevas terapéuticas que resultan efectivas en casos reportados en la literatura, sin que aún se hayan podido definir guías de manejo para este tipo de pacientes. Se necesita realizar estudios de terapéutica en pacientes refractarios a esteroides para poder concluir al respecto.

Graft versus host disease is a condition of frequent occurrence in people who are implanted with allogeneic transplants. The diagnosis is clinical, supported by histopathology, but this, by itself does not make a diagnosis. The first line of treatment for this entity are systemic steroids. For the patient refractory to systemic steroids, new therapeutics that could be useful are reported, but not yet defined its use and none were superior to steroids. Studies are needed to define the approach to the patient refractory to steroids.

Blood and marrow transplantation: a perspective from the University of Minnesota.

On the occasion of the first meeting of the Robert A. Good Immunology Society in June of 2006, I was asked to provide a perspective on the history and progress of the field of bone marrow transplantation. I was honored to provide this perspective at that meeting and subsequently in this manuscript. This review has a strong University of Minnesota bias, as Minneapolis is a place where important roots in this field were developed. Minnesota is also where I have spent my career in this field learning the excitement of laboratory research beginning as a medical student under Bob Good and Carlos Martinez in 1960, and clinical research in pediatrics under Bill Krivit and Mark Nesbit beginning in 1970. This review is dedicated to two of my recently deceased mentors: Bob Good was a pioneer in so many ways and a true giant in immunology and blood and marrow transplantation. Bill Krivit taught me a great deal about genetic diseases and the critical role of compassion and understanding patients and their families in dealing with fatal illness and new treatments such as bone marrow transplantation that are often risky and themselves may result in suffering and death. My affection for Bob Good and Bill Krivit is unending.

Crossing barriers in transplantation.

In 1978, Jonathan Sprent and Robert Korngold proved that graft-versus-host disease (GVHD) is caused by donor T cells that attack the host's non-MHC antigens. T cell depletion of donor grafts has since become a staple of transplantation strategies to combat leukemia and other inherited blood disorders.

History of the clinical use of umbilical cord blood hematopoietic cells.

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?

Bone marrow transplantation: a review.

Bone marrow transplantation has evolved over a period of 50 years. Laboratory observations and animal studies defined the essentials of transplantation biology. The first attempts to transfer these studies to patients met with little success. The definition of the complexities of the human leukocyte antigen (HLA) system made it possible to select compatible sibling donors and more recently unrelated donors. Transplantation of stem cells from marrow, blood, or cord blood is now the treatment of choice for a variety of hematological and genetic diseases. Transplantation using less toxic preparative regimens to induce mixed chimerism makes possible an application to autoimmune diseases. Laboratory and clinical research directed toward induction of tolerance and elimination of malignant cells point the way to a wider application of hematopoietic cell transplantation in the next decade.

The evolution of clinical peripheral blood stem cell transplantation.

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.

Acute graft-versus-host disease: clinical characteristics in the cyclosporine era.

Graft-versus-host disease (GVHD) remains the major problem in allogeneic bone marrow transplantation. GVHD has limited the use of this technique to HLA-matched donor recipient pairs. Thus, only a quarter of patients who ultimately may have benefited from bone marrow transplantation are currently eligible. Even in matched patient recipient pairs, GVHD accounts for approximately 40% of the deaths following allogeneic bone marrow transplants. One of the major challenges for transplantation is to derive better strategies to prevent and treat GVHD while retaining the allogeneic benefit of graft-versus-leukemia. Current pharmacologic approaches have used cyclosporine, usually in combination with other drugs. More experimental approaches have removed lymphocytes from the marrow grafts. With either approach, maintaining the anti-leukemic benefit of an allogeneic transplant (i.e., immunologic attack of the leukemia resulting in a lower relapse rate), will need to be maintained if that approach will ultimately prove to be useful.