BONE-MARROW FAILURE - PATHOPHYSIOLOGY AND MANAGEMENT - FOREWORD

Morphologically, bone marrow is made up of a relatively mature but het erogenous population, fueled by a tiny pool of microscopically unrecog nizable stem and progenitor cells. This complex tissue has the respons ibility of maintaining our hematopoietic and, to a large extent, immun ologic integrity, both of which are indispensable for health and, inde ed, survival. Perhaps not surprisingly, bone marrow is the target of g enetic, autoimmune, and environmental insults. Although robust, it has only a limited number of responses, one of which is reduction in cell ular output, sometimes with superimposed qualitative abnormalities, an d this is defined as bone marrow failure. Bone marrow failure is a div erse entity but can be logically explained and classified on a pathoph ysiologic basis. Thus the major recognizable categories of bone marrow failure are congenital and acquired defects. Each of these is subdivi ded according to the number of cell lines involved, over and above whi ch the severity of the damage will determine reversibility. In each ca se, the natural history dictates management, and this ranges from shor t-term growth factor support to biologic immune response modulation an d finally to bone marrow transplantation. In the past, many clinicopat hologic variants of bone marrow failure were described, although their etiology was obscure and effective therapy was unavailable. This chan ged dramatically, however, when experimental hematologists, using radi obiology models, uncovered the dynamic nature of blood formation. Card inal observations included the way in which spontaneous recovery follo wed irradiation, the central role played by pluripotential stem cells, and the integral participation of stroma in modulating this entire pr ocess. Understanding was refined once bone marrow cultures became avai lable while, in paralle, the use of in-bred mouse strains launched the era of allogeneic transplantation. These approaches were combined, an d the broad principles that govern basal or constitutive production em erged. Stem cells, with their characteristic commitment to self-renewa l, exist at the apex of a hierarchy and generate a tier of proliferati ng progenitors that, in turn, give rise to a large postmitotic compart ment of precursors that mature into distinctive myeloid and lymphoid l ineages. The reserve potential is enormous, and output can be induced to meet even greatly increased demands. These events reflect the inter action of growth factors with a balancing set of negative regulators. The link between such diverse functions resides, to a large extent, in accessory cells and matrix geographically organized in what is now de scribed as the hematopoietic inductive microenvironment. Many details of these meticulously orchestrated processes are obscure. For example, how are adhesion proteins, expressed on vascular endothelium, subtly altered to facilitate release of mature cells into the circulation? En igmatic also is the way in which membrane antigens change during recov ery from chemotherapy or in response to growth factors, so that early progenitors flood the circulation and can be collected for subsequent autografting. In spite of our new-found knowledge, patient management is often empiric. To illustrate this point, consider the inherited Jos ephs - Diamond - Blackfan anemia or global aplasia described by Fancon i, in which undoubted benefit - indeed cure - is possible with the non selective transplantation of marrow. Our understanding of this process is rather crude and is a far cry from the exquisite specificity with which a solitary molecular defect, once defined, can be repaired using gene therapy. Patients with acquired lesions are little better off. S ome, such as those with idiopathic pure red cell aplasia, enjoy sponta neous remission, whereas others require varying degrees of pharmacolog ic immunosuppression. Perhaps more frustrating are the many cases of u nexplained loss of hematopoietic tissue. It has been suggested that su ch individuals have a genetically fragile marrow that collapses when s ubjected to a relatively minor environmental insult and that possibly the collapse is acting through an immunologic mechanism. For want of a precise molecular diagnosis, the same relatively unsophisticated ther apeutic approaches are used in these patients, albeit with substantial success. In this context, allogeneic transplantation is limited by re jection, whereas stable engraftment may be tarnished by the not insign ificant incidences of morbidity and mortality that result from graft-v ersus-host disease. Unfortunately, even this option is not always avai lable, and alternatives such as antilymphocyte globulin, which do brin g about quantitative responses, may be followed by the later developme nt of myelodysplasia or acute leukemia. These obvious shortcomings pro mpted investigators to study closely the convoluted trail that leads b ack to faulty DNA to allow more exact intervention. Against this backg round, there arises the question of how to structure a pragmatic and r elatively uniform approach to the care of patients with bone marrow fa ilure. Logically, treatment modalities should center on the currently understood model of hematopoiesis, in which lesions can arise in early stem cells, resulting in aplasia. This is in contrast to the damage o f already committed progenitors in which, at least initially, single l ineages are affected. Within each category, the defect may be inherite d or acquired. Approached pathophysiologically, an algorithm for treat ment evolves naturally and advocates simple support for those in whom spontaneous recovery is predicted, although this increasingly incorpor ates the use of recombinant human growth factors or interleukins, whic h are often given together. For irreversible damage, bone marrow trans plantation is currently the treatment of choice. If this option is lac king, immuno-suppressive regimens are effective, with the caveat that complications must be anticipated. The future is somewhat brighter, wi th the promise that more precise molecular diagnosis is, in many cases , well within our grasp. Armed with such vital information, gene thera py becomes a realistic possibility; precedent already exists in which adenosine deaminase deficiency, an otherwise lethal immunologic disord er, can be precisely corrected.