A hole you can drive a MAC through

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2001 97: 2533 doi:10.1182/blood.V97.9.2533a

A hole you can drive a MAC through Dan L. Longo

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Treatment of adults with ITP: less may be more

75% of splenectomy patients were in remission at 2 years and 66% remained in remission at 10 years. —John G. Kelton

Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disorder managed by hematologists often outside of tertiary care centers. Yet despite its relative commonness, its natural history has not been studied systematically. Ironically, the paucity of studies of ITP subtly supports the concept of its benign nature. In contrast to patients with acute leukemia, patients with ITP are often managed in the community, where data collection is difficult. Portielje and colleagues (page 2549) follow 152 patients with ITP who were managed in a consistent fashion. Their analysis of the outcome at 2 and 10 years after diagnosis should give us comfort. Most patients (85%) achieved a safe platelet count (above 30 000/␮L) off all therapy, and these patients had the same 10-year mortality as the general population. Nine percent of the patients had severe and refractory disease, and their overall mortality was 4.2%, with death caused equally by bleeding (the disease itself) and by infection (often secondary to the treatment). A further 6 percent of patients maintained a safe platelet count on maintenance therapy. These investigators concluded that most patients with ITP have a good outcome without excess morbidity or mortality. Their study further supports the growing practice of avoiding aggressive therapy in ITP patients with mild to moderate thrombocytopenia. The study answers some questions but raises others. What is the explanation of the surprisingly high rate (26%) of postoperative complications of splenectomy? I suspect that laparoscopy splenectomy will prove to have a lower morbidity. The study also confirms the centrality of splenectomy as the current definitive treatment for ITP. Portielje and colleagues demonstrate that

BLOOD, 1 MAY 2001 䡠 VOLUME 97, NUMBER 9

McMaster University

A hole you can drive a MAC through The complexity of host defense mechanisms is awe inspiring. A wide range of cell types can interact and produce an enormous spectrum of products that work together to protect the organism against the hostile environment in which it lives. The network of host defense is sufficiently fine-meshed and redundant that a very small fraction of all the possible hostile invaders sneak through it under normal circumstances. Two kinds of observations assist us in understanding the role of individual components of host defense in the complex interworkings: (1) experimental work (for example, we create knockout mice in which a single component of the system is removed or damaged and the resulting phenotype carefully characterized) and (2) careful observation of human illnesses. If one can understand the pathophysiologic basis for the existence of a particular hole in the network, insights about the entire system emerge. Sakai and colleagues (page 2688) define the error in host defense that made a young man susceptible to disseminated Mycobacterium avium complex (MAC). They found that the patient was unable to produce interferon gamma (IFN-␥) as a consequence of an inability to respond to interleukin-12 (IL-12). The IL-12 unresponsiveness was due to a mutation in the IL-12␤1 gene (tryptophan substituting for arginine at position 213, or R213W in the vernacular) that resulted in the rapid proteolysis of the mutant gene product and defective IL-12 receptor expression and function. A prior report had suggested that Q214R mutation of the same gene produced an immune deficiency state, but

Sakai and colleagues find this mutation existing in otherwise normal people as a polymorphism in a normally functioning receptor. Thus the redundancy in host defenses does not extend to IL-12–induced IFN-␥ production. Defective IL-12 receptors create a specific vulnerability to MAC. How widespread this disease may be is yet to be determined. —Dan L. Longo National Institutes of Health

Punching holes in GVHD and GVL T lymphocytes contained within an allogeneic stem cell transplant for leukemia are a force for both good and evil. T cells significantly decrease the incidence of disease relapse by killing leukemic cells (graftversus-leukemia effect, or GVL) while simultaneously causing often life-threatening graft-versus-host disease (GVHD). Whether these processes are fundamentally different enough that GVHD can be abrogated while GVL is preserved, by such approaches as depletion of T-cell subset and manipulation of cytokines thought to induce (eg, TNF) or inhibit (eg, IL-11) the inflammatory GVHD response, has been uncertain. Schmaltz and colleagues (page 2886) now show that distinct T-cell effector pathways can preferentially cause GVL, but not GVHD. Using a mouse parent–into–F1 bone marrow transplantation model, congenic strains deficient in FasL or the granule protein perforin, and 2 myeloid leukemic cell lines, they find that the Fas/FasL pathway is critical to the appearance of GVHD but not to antileukemic T-cell killing. Even though both leukemic lines express Fas and can be killed by cell lines expressing FasL in vitro, GVL does not require Fas/FasL in vivo. Perforin-deficient T cells, in contrast, provide little detectable GVL but still cause GVHD. These findings, if validated in other stem cell transplantation models, suggest

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