IL-11 is a unique growth factor derived from cells making up the HM. Although cloned based on IL-6-like bioactivity, IL-11 and IL-6 have distinct biologic profiles (Table 1). IL-11, like many recently cloned growth factors, has pleiotropic effects on hematopoietic cells presumably depending on the cytokine and cellular environment into which it is introduced. However, some general findings are consistent (Table 2). In addition, IL-11 has significant effects, either primary or secondary, on nonhematopoietic cells, including neurons, small intestine crypt progenitor/stem cells, and preadipocytes. The institution of human trials with IL-11 will provide important information on the pharmacologic effects of IL-11 on human hematopoietic cells in the context of frequently used chemotherapy protocols. The physiologic role(s) of IL-11 are unknown but will become clear (at least in the mouse) with gene targeting experiments underway in several laboratories.

There is now substantial evidence that a small group of V genes predominates in the Ig repertoire of preimmune B cells. This phenomenon of V gene restriction may reflect preferential accessibility of these genes to recombinase, homology-directed V gene rearrangement, promoters and enhances of V gene transcription, or positive and negative selection mediated by the anti-self binding properties of the B cells surface Ig. These mechanisms may operate alone or in combination to influence V gene rearrangement and populations of immature B cells. Although constraints on the pool of rearranged V genes may seem disadvantageous to the immune system, the mechanisms that generate the CDR3s of heavy and light chains ensure extensive diversity in the pre-B-cell population. In mature B cells, somatic mutation of V genes adds further diversity. CDR3 sequences and somatic mutations not only provide potentially useful clonal markers but also help to identify the normal counterparts of malignant B cells.

As the above-mentioned cellular and molecular parameters and newly identified biologic features are evaluated in larger numbers of patients with aggressive NHL, the biologic heterogeneity of this disease will be better appreciated. With a more complete understanding of the disease, it is likely that we will substitute biologic variables for clinical surrogate features in our prognostic factor models and target these biologic variables for therapy in specific subsets of patients. In the meantime, widely accepted clinical models such as the International Index and the age-adjusted index will aid in the identification of specific patient risk groups and the ongoing comparison of different therapeutic approaches. Early restaging with sensitive techniques like Ga-67 citrate scans may also identify patients with suboptimal responses to induction therapy at timepoints when additional therapeutic alternatives may be most effective.

The recent discovery of molecular defects in three forms of X-linked immunodeficiency has quickly transformed the study of immunodeficiency into one of the most exciting in basic and clinical immunology. The identification of defects in the IL-2R gamma chain in the etiology of X-linked SCID has suggested a heretofore unanticipated functional role of the gamma chain in immunologic development. While new and novel cytokines and cytokine receptors continue to be identified, it has become clear that our knowledge of IL-2, one of the best understood cytokine/receptor systems, is far from complete. Clarifying the molecular interactions between IL-2 and its receptor complex will improve the sophistication with which these interactions are manipulated in the clinic for the treatment of autoimmune disorders and allograft rejection, treatment of lymphoid malignancies, and cytokine-based therapies for immunotherapeutic treatment of nonlymphoid cancers. Recent gene therapy approaches to the treatment of children with the ADA-deficient form of SCID offers yet another exciting path for investigation. The use of retrovirally infected cord blood hematopoietic progenitor cells in attempts to reconstitute the immune system of ADA-deficient SCID children with ADA-producing cells raises the possibility of similarly "correcting" the defect in X-linked SCID. Such approaches almost certainly loom on the near horizon for other diseases. However, in view of the complexity and potentially pleiomorphic nature of defects in the IL-2R gamma chain, both in terms of their identification and correction, gene therapy for treatment of X-linked SCID will require a thorough understanding of the molecular nature of the respective defects. Effective therapy will require precise knowledge of the defects, in terms of their influence on the ligand, receptor, and signaling apparatus, as well as their potential effects on cells of multiple lineages. However, these caveats aside, the potential for understanding and correcting a disease that robs infants at so early an age of the potential for a normal life will continue to make these exciting and extraordinarily rewarding pursuits.