Chimerism Hematopoietic

Yair Reisner, Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

The ancient Greek chimera, that awesome monster composed of different animals, has in modern times been tamed, and now represents a most desirable clinical status in recipients of organ transplants in general, and bone marrow transplants in particular. Thus, the term chimerism has come to represent a clinical status in which a graft of an organ from one individual is accepted and tolerated by the immune system of another. While acceptance of solid organs, such as kidney, heart or liver, is largely dependent on adequate suppression of the recipient's immune system, as well as on the degree of matching between donor and recipient histocompatibility antigens, bone marrow transplantation is unique in that, in most instances, incomplete or mixed hematopoietic chimeras are generated, and both host-type and donor-type blood cells can be detected in the recipient. Furthermore, while immune reactivity against donor type cells is an obstacle to bone marrow engraftment in all transplants, bone marrow transplantation is uniquely complicated by a second immune barrier, known as graft-versus-host disease (GVHD), mediated by donor type T cells reactive to host antigens.

A successful bone marrow transplant results in a state of hematological and/or immunological chimerism in which donor-type blood cells coexist permanently with host-type tissues, without manifesting alloreactivity to each other. If such a state of tolerance is achieved, subsequent organ grafts from the original bone marrow donor will be accepted without the need to further suppress the recipient's immune system. For this reason, investigation of the mechanisms of tolerance, as well as new and safer approaches for its induction, have challenged immunologists for over three decades.

Currently, bone marrow transplantation is mainly used as a rescue therapy following lethal radio-chemotherapy in patients with leukemia and other forms of cancer, but it can also be beneficial in the treatment of several nonmalignant hematological disorders and enzyme deficiencies.

The first demonstration that a bone marrow transplant could protect lethally irradiated animals from death came from the pioneering studies of Jacobson and colleagues and Lorenz and colleagues towards the beginning of the 1950s. However, it was only in 1956 that several laboratories independently confirmed that a cellular component of the transplanted bone marrow protected recipient mice from the lethal effects of radiation, by its ability to generate new donor-type blood cells for prolonged periods of time.

A better understanding of the bone marrow cellular identity involved in radioprotection was achieved by Till and McCuloch, who discovered a correlation between the presence of spleen colonies in transplanted mice 8-12 days after bone marrow transplantation and the capacity of a given bone marrow cell suspension to protect lethally irradiated mice. This finding helped Trentin and Fohlberg to demonstrate that the entire repertoire of the hematopoietic system could be generated from a single spleen colony. By 1963, Becker and coworkers were able to use chromosome markers to demonstrate the clonal nature of spleen colonies. The existence of a pluri-potent stem cell, and its importance in the protection of lethally irradiated mice, thus came to be postulated.

To this day, the characterization of the pluripotent hematopoietic stem cell has been the subject of intense research. With the identification of new cell surface markers, great progress has recently been made. However, since these cells have not been purified to a homogeneous state, they cannot be unequivocally identified in a bone marrow cell suspension.

Knowledge of the radioprotective properties associated with bone marrow transplantation found dramatic application in 1955, when five victims of the radiation accident in Vinca, Yugoslavia were flown to Paris and treated by Mathe and colleagues with bone marrow transplants. Due to technical problems in analyzing the origin of blood cells in these patients, interpretation of results was controversial, but it was agreed that, at best, some transient engraftment occurred, and could have helped the patients to survive, even though their own blood cells returned to normal levels. Fortunately for these patients, they did not suffer from GVHD, as the transplanted bone marrow did not engraft for a substantial period of time.

In the late 1960s, encouraged by the development of histocompatibility antigen (HLA) typing, it was felt that it might be possible to contain the severity of GVHD by transplanting bone marrow from matched sibling donors into patients with severe combined immune deficiency (investigated by Good and colleagues) and leukemia (investigated by Thomas and colleagues). Both groups experienced many frustrating setbacks in their attempts to achieve stable chimerism, but it is primarily due to their perseverance that bone marrow transplantation has now become an integral part of the curative protocol used to treat such patients.

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