Immunity, Vol. 14, 105110, February, 2001, Copyright 2001 by Cell Press

Contrasting Roles of IL-2 and IL-15Minireview

in the Life and Death of Lymphocytes:

Implications for Immunotherapy

Thomas A. Waldmann,* Sigrid Dubois,

and Yutaka Tagaya

Metabolism Branch

National Cancer Institute

National Institutes of Health

Bethesda, Maryland 20892

Although IL-2 and IL-15 share two receptor subunits and many functions, especially in innate immunity, at times they provide distinct and contrasting contri-butions to T cellmediated immune responses. IL-2, through its pivotal role in activation-induced cell death (AICD), is involved in peripheral tolerance through the elimination of self-reactive T cells. In contrast, in general IL-15 manifests antiapoptotic actions and inhibits IL-2-mediated AICD and stimulates persistence of memory phenotype CD81 T cells. Humanized monoclonal anti-bodies that recognize IL-2Ra, the private receptor for IL-2, are being employed to inhibit allograft rejection and to treat T cell leukemia/lymphoma. Therapies directed toward inhibiting the actions of the inflammatory cyto-kine, IL-15, have been proposed for an array of autoim-mune disorders as well as diseases associated with the retrovirus HTLV-I.

A major advance in receptor-directed therapy for many human diseases using monoclonal antibodies was the definition of new cell surface structures as targets for more effective mAb action. One such target for more specific immune suppression in transplantation, autoim-munity, and T cell leukemia is the high-affinity IL-2 re-ceptor, since its expression marks a critical step in the activation of T cells. The scientific basis for the choice of this target is that resting normal cells do not express IL-2Ra, whereas this receptor subunit is expressed by a proportion of the cells involved in allograft rejection, those participating in select autoimmune diseases, and by the abnormal cells in certain lymphoid neoplasias (Waldmann, 1991).

In part as an outgrowth of IL-2R-directed therapeutic trials, two groups simultaneously reported the identifica-tion of a T- and NK-stimulating cytokine, IL-15 (Burton et al., 1994; Grabstein et al., 1994). In T cells, the IL-15 receptor includes IL-2Rb and gc subunits shared with IL-2 (Bamford et al., 1994; Grabstein et al., 1994), as well as an IL-15- specific receptor, IL-15Ra (Giri et al., 1995). As might be anticipated from their sharing of the IL-2Rb and gc subunits, IL-15 and IL-2 share a number of biological activities. However, especially in adaptive immune responses, they also provide distinct, at times competing, contributions to the life and death of lym-phocytes involved in the immune response (DiSanto, 1997; Ku et al., 2000; Marks-Konczalik et al., 2000; Mar-rack et al., 2000). These distinct roles for IL-2 and IL-15 in the survival of lymphocytes, including those that are self-reactive as well as lymphocytes that maintain immu-

* E-mail: tawald@helix.nih.gov.

nological memory to foreign pathogens, have significant implications for the development of rational receptor-directed therapeutic approaches that focus on the IL-2/IL-2R or, alternatively, the IL-15/IL-15 R systems.

IL-2 and IL-15 in the Life and Death of Lymphocytes

The immune system is dedicated toward a series of goals, including (1) the generation of rapid innate (e.g., NK cell) and adaptive (e.g., antibody and T cell) re-sponses to invading pathogens, (2) the maintenance of a specific memory response to these pathogens, and

(3) the elimination of autoreactive T cells to yield toler-ance to self. Such immune responses are regulated by a series of cytokines that exhibit a high degree of redun-dancy and pleiotropy. For the IL-2 family of cytokines that includes IL-2 and IL-15, this redundancy is ex-plained by the sharing of common receptor subunits. The common g chain (gc) is shared by IL-2, IL-4, IL-7, IL-9, and IL-15 (Lin et al., 1995). IL-2 and IL-15 also share the IL-2Rb subunit (Bamford et al., 1994; Grabstein et al., 1994). Finally, the high-affinity forms of the IL-2 and IL-15 receptors also involve the private receptor sub-units, IL-2Ra and IL-15Ra, respectively (Waldmann, 1991; Giri et al., 1995). As a consequence of their sharing of the receptor elements IL-2Rb and gc and their use of common Jak/STAT signaling elements, IL-2 and IL-15 also share a number of functions including the stimu-lation of the proliferation of activated CD42, CD82, CD4181, CD41, CD81, and gd subsets of T cells (Grabstein et al., 1994; Waldmann and Tagaya, 1999). Furthermore, the two cytokines facilitate the induction of cytolytic effector T cells including CTL and LAK cells and induce the proliferation and immunoglobulin syn-thesis by B cells stimulated by anti-IgM or CD40 ligand (Armitage et al., 1995). They also stimulate the genera-tion, proliferation, and activation of NK cells. In addition to these shared functions there are, however, distinct differences between IL-2 and IL-15 that are especially critical in the homeostasis of adaptive immune re-sponses.

Distinct Actions of IL-2 and IL-15 in AICD and in the Survival of Memory Phenotype CD81 T Cells

Recent ex vivo functional analyses as well as studies using transgenic mice and those genetically lacking IL-2, IL-15, or their specific receptors have been of particular value in the definition of the distinct roles played by IL-2 and IL-15 (Sadlack et al., 1994; Willerford et al., 1995; Lodolce et al., 1998; Kennedy et al., 2000) (Figure 1). Although IL-2 is an important growth and survival factor, it also plays a pivotal role in Fas-mediated AICD of CD4 T cells (Lenardo, 1996; Refaeli et al., 1998; Van Parijs et al., 1999). Receptor-mediated stimulation of CD4 T cells by antigen at high concentrations induces the expres-sion of IL-2 and the IL-2 receptor that in turn interact to yield T cell activation and cycling. Antigen restimulation of the cycling T cell at this stage through the T cell antigen receptor increases the transcription and surface expression of the death effector molecule Fas ligand (Fas L) and suppresses an inhibitor of Fas signaling FLIP (Refaeli et al., 1998). Activation of STAT 5 by IL-2 was reported to be involved in T cell proliferation, the induc-

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Figure 1. Diagrammatic Model Outlining the Distinct Roles Played by IL-2 and IL-15 in the Life and Death of T Cells

IL-2 is required for AICD involved in peripheral tolerance to self-antigen whereas IL-15 inhib-its this process. In addition, IL-15 supports whereas IL-2 inhibits the survival of memory phenotype CD81 T cells.

tion of Fas L expression, and AICD, whereas T cell sur-vival was dependent on an IL-2Rb region that is involved in the activation of Akt and the expression of Bcl-2 (Van Parijs et al., 1999). IL-15 in contrast acts to extend the survival of lymphocytes by acting as a growth factor and by inhibiting IL-2-mediated CD41 T cell AICD (Marks-Konczalik et al., 2000). The mechanism underlying this inhibition of the AICD phemonenon has not been de-fined. In ex vivo studies, CD41 T cells from IL-15 trans-genic mice did not manifest IL-2-induced AICD. Of inter-est in these studies, there was the additional observation that the inclusion of an anti-IL-15 antibody to the ex vivo cultures resulted in the restoration of the ability of IL-2 to induce AICD of the CD41 T cells derived from the IL-15 transgenic mice (Marks-Konczalik et al., 2000). In some cases, the anticell death action of IL-15 was associated with the induction of a quiescent phenotype characterized by the maintenance of the cells in the G0/ G1 phases of the cell cycle with downregulation of CD25 and CD95 expression (Dooms et al., 1998, 2000). How-ever, in the presence of appropriate TCR engagement, the IL-15-induced quiescent cells were both resistant to TCR-induced cell death and proliferated strongly in response to IL-15. Thus, IL-15 may play a role in the promotion of long-term maintenance of antigen-express-ing CD41 T cells. In addition to its role in inhibiting the AICD of CD41 cells, IL-15 has been reported to manifest an antiapoptotic action in a number of other lymphoid systems; for example, it inhibited dexamethasone and anti-IgM-mediated apoptosis of activated B cells as well as the spontaneous apoptosis of CD4 and CD8 cells in HIV-infected individuals by a mechanism involving Bcl-2 (Naora and Gougeon, 1999).

In addition to their actions in AICD, IL-2 and IL-15 play opposing roles in the control of the homeostasis of CD81 memory phenotype T cells. Zhang and coworkers (Zhang et al., 1998) demonstrated that unlike IL-2, IL-15 provides potent and selective stimulation of memory-phenotype (CD44hi) CD81 T cells in vivo. Furthermore, Ku, Marrack, and coworkers (Ku et al., 2000; Marrack

et al., 2000) reported that the division of CD81 T cells of memory phenotype is stimulated by IL-15 but is inhib-ited by IL-2.

These conclusions derived from ex vivo functional studies are supported by an analysis of mice with dis-rupted cytokine and cytokine receptor genes as well as transgenic mice. IL-22/2 and IL-2Ra2/2 null mice devel-oped massive enlargement of peripheral lymphoid or-gans associated with polyclonal T and B cell expansion, which for T cells was related to impaired ACID (Sadlack et al., 1994). The IL-2Ra-deficient mice developed auto-immune diseases including hemolytic anemia and in-flammatory bowel disease (Willerford et al., 1995). This autoimmune phenotype observed in the IL-2R-deficient mouse leads to a concern about the use of IL-2Ra-directed monoclonal antibodies for the treatment of autoimmune diseases. In contrast to the phenotype observed with IL-2-deficient mice, mice genetically deficient in interleukin-15 (IL-152/2) did not manifest lymphoid enlargement, high immunoglobulin levels, or autoimmune disease (Kennedy et al., 2000). Rather, they displayed a marked reduction in the numbers of thymic and peripheral natural killer (NK) cells, NK T cells, and intestinal intraepithelial lymphocytes (IELs). Further-more, they manifested a marked reduction in memory phenotype CD81 T cells. IL-15Ra-deficient (IL-15Ra2/2) mice also showed a profound defect in NK cells, TCR intraepithelial lymphocytes as well as memory pheno-type CD81 T cells that was associated with profound generalized lymphocytopenia (Lodolce et al., 1998). In contrast, IL-15 transgenic mice manifested an inhibition of IL-2-mediated AICD and an increased number of NK cells and memory type CD81 cells (Marks-Konczalik et al., 2000). These mice were not reported to manifest autoimmune disease. Taken together, these studies support the view that in their special adaptive immune functions IL-2 and IL-15 favor opposing actions that tend to emphasize one or the other of two competing major goals of the immune response. IL-2 through its contribution to AICD for CD4 cells and its interference

Minireview 107

with the persistence of CD81 memory phenotype T cells favors the elimination of select lymphocytes that are directed toward self-antigens and thus plays a critical role in the maintenance of peripheral self-tolerance. In contrast, IL-15 through its inhibition of IL-2-mediated AICD and its role in the maintenance of CD81 memory phenotype T cells favors the maintenance and survival of CD4 and CD8 T cells. The persistence of memory phenotype CD81 T cells should be of value in main-taining a specific immune response to foreign patho-gens. However, it carries with it the risk to the organism of the survival of autoreactive T cells that could lead to the development of autoimmune diseases. Indeed, it has been reported that IL-15 overexpression is associ-ated with an array of inflammatory autoimmune dis-eases. To circumvent this risk of autoimmune disease, there is a multifaceted control of IL-15 expression (Grabstein et al., 1994; Bamford et al., 1996; Azimi et al., 1998; Waldmann and Tagaya, 1999). In particular, in addition to control at the level of transcription IL-15 is posttranscriptionally regulated by multiple controlling elements that impede translation, including 1113 up-stream AUGs in the different 59 UTR isoforms, two un-usual signal peptides, and the C terminus of the mature protein (Bamford et al., 1998; Waldmann and Tagaya, 1999). The variety of negative regulatory elements con-trolling IL-15 expression may be required because of the potency of IL-15 as an inflammatory cytokine. With its capacity to inhibit AICD, to perpetuate memory phe-notype CD81 cells, and to induce the expression of cyto-kines and chemokines involved in the inflammatory re-sponse if indiscriminately expressed, IL-15 could be associated with serious disorders including autoim-mune diseases (McInnes et al., 1997). In terms of a more positive role for IL-15, we propose that by maintaining a pool of translationally inactive IL-15 mRNA diverse cells may respond rapidly to an intracellular infection or other stimulus by transforming IL-15 mRNA into a form that can be translated effectively. The IL-15 protein pro-duced and secreted could convert T and NK cells into activated killer cells that might provide an effective host response to an invading infectious organism.

A critical issue that remains to be resolved is how two cytokines, IL-2 and IL-15, that share two signaling receptor subunits and utilize a common Jak3/STAT5 signaling pathway manifest a number of contrasting functions. Many alternatives have been suggested as explanations for these differences. The two cytokines are produced by quite different cells and tissues (Wald-mann and Tagaya, 1999). Their synthesis and secretion are controlled in distinct fashions. Furthermore, their private specific receptors, IL-2Ra and IL-15Ra, have different cellular distributions. In particular, IL-2Ra and the high-affinity IL-2 receptor are predominantly ex-pressed on activated monocytes T, B, and NK cells. However, the high-affinity IL-15 receptor and all eight isoforms of IL-15Ra have a much wider cellular distribu-tion. IL-15R expression is observed in T cells, B cells, macrophages, and in thymic and bone marrow stromal cell lines as well as in such tissues as liver, heart, spleen, lung, skeletal muscle, and activated vascular endothelial cells. This widespread distribution is one of the mecha-nisms underlying the pleiotrophy of IL-15 and may con-tribute to the differences in IL-2 and IL-15 action. In

addition, a second IL-15 binding and signaling pathway that does not share any subunits with the IL-2R system has been defined (Tagaya et al., 1996). This novel IL-15R system uses a signal transduction pathway distinct from that used by IL-2. Furthermore, IL-15 was shown to deliver a nonproliferative functional signal to colonic cells in the absence of IL-2Rb (Stevens et al., 1997). However, it must be emphasized that this IL-15 receptor/ signaling pathway has been demonstrated in mast cells but not as yet in T cells. Another distinction between IL-2 and IL-15 is in their binding interactions with IL-2Rb. Antibodies directed toward this receptor subunit such as Mikb1 block the functional effects of IL-15 but not those of IL-2. More likely explanations for the distinct actions of IL-2 and IL-15 focus on the private cytokine-specific receptor elements IL-2Ra and IL-15Ra. It has been suggested that the response to the cytokines de-pends not only on the interactions of the subunits with the ligand but also on the interactions among the three subunits themselves. In this regard, the proximity of the distinct subunits to IL-2Ra alters the conformation of signaling elements of the receptors in distinct ways, thereby altering the nature of the cytokine-mediated sig-nals transmitted to the nucleus. For example, we and others demonstrated that the proximity of the IL-2Ra subunit changes the function of the IL-2Rb subunit to alter IL-2 binding and signaling by mechanisms that do not require binding of IL-2 to the IL-2Ra subunit (Arima et al., 1991; Grant et al., 1992; Kuziel et al., 1993). Finally, there may be distinct signals to the nucleus from the private receptor subunits or from other proteins nonran-domly associated with them. For example, it has been reported, but as yet not confirmed, that following IL-15 addition there is a recruitment of TRAF 2 and Syk kinase to the 37 amino acid cytoplasmic tail of the IL-15Ra chain (Bulfone-Paus et al., 1999).

IL-2- and IL-15-Directed Immunotherapy

for Leukemia/Lymphoma, Select Autoimmune Diseases, and to Prevent Allograft Rejection

IL-2R as a Target for Immunotherapy. Most IL-2/15R-directed therapeutic approaches have targeted the IL-2Ra subunit (Waldmann et al., 1993; Vincenti et al., 1998; Waldmann and OShea, 1998). The scientific basis for this target choice is that IL-2Ra is not expressed by normal resting cells but is constitutively expressed by the malignant cells in an array of T and B cell leukemias, by T cells involved in select autoimmune diseases, and by those T cells that participate in organ allograft rejec-tion. Early human clinical trials involving IL-2Ra-directed therapy focused on HTLV-I-associated adult T cell leu-kemia (ATL). The retrovirus HTLV-I encodes a 42 kDa protein termed tax that is responsible for the transactiva-tion of numerous host genes including those encoding IL-2, IL-2Ra, IL-15, and IL-15Ra that are involved in T cell activation and, potentially, HTLV-I-mediated leuke-mogenesis (Azimi et al., 1998). In the early phases of the disease in patients with ATL, there is evidence sup-porting an autocrine loop involving IL-2 and IL-2Ra that participates in the expansion of the leukemic cells (Maeda et al., 1987). We demonstrated that therapy with an unmodified murine version of the anti-Tac mAb that blocks the binding of IL-2 to IL-2Ra led to a partial or complete remission in 6 of the 19 patients with ATL treated (Waldmann et al., 1993). Effective action of this

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monoclonal antibody in some cases appears to be due to the interdiction of the interaction of IL-2 with its growth factor receptor leading to cytokine deprivation-mediated apoptotic cell death. However, neither IL-2 mRNA nor IL-2 protein is expressed in the later phases of acute ATL including some cases where anti-Tac has provided effective therapy. In these cases, prevention of autocrine stimulation by blocking IL-2 interaction with IL-2R could not be the mode of effective antibody action. Furthermore, IL-2Ra-directed monoclonal antibodies were shown to provide effective therapy in a murine model of human ATL by an FcR-requiring mechanism other than blockade of IL-2/IL-2R interaction (Phillips et al., 2000). In these cases, effective action that requires the complete antibody may involve its binding to the FcRIII present on monocytes and macrophages. This conclusion is in accord with those emerging from the elegant studies of Clynes and coworkers that demon-strated that FcR-I and/or III are required for effective in vivo monoclonal antibody action against tumor targets in many systems including those directed toward HER-2 neu using trastuzumab or toward CD20 using retuximab (Clynes et al., 2000).

A humanized antibody to IL-2Ra (humanized anti-Tac, daclizumab) was generated that addressed limitations inherent in the use of the murine version of this mono-clonal antibody including its immunogenicity, its ineffec-tiveness in recruiting human host-effector functions, and its short in vivo survival (Queen et al., 1989). Follow-ing encouraging results in animal models and in phase I/II trials, two phase III randomized, placebo-controlled clinical trials were performed that included 535 evalu-ated patients to determine the value of humanized anti-Tac (daclizumab, Zenapax) in the prevention of renal allograft rejection (Vincenti et al., 1998). In each trial, patients received placebo or daclizumab in addition to the standard immunosuppressive regimen. The acute graft rejection rate at 6 months was significantly lower, and renal allograft retention was significantly higher in the patients treated with daclizumab (p # 0.01). On the basis of these phase III trials, FDA approval was ob-tained for the use of daclizumab in the prevention of acute kidney transplant rejection. In a similar extensive randomized trial, it was shown that basiliximab, a chime-ric antibody also directed toward IL-2Ra, was associ-ated with reduced numbers of acute rejection episodes in renal allograft recipients (Nashan et al., 1997). This agent also received FDA approval for the prevention of renal allograft rejection. In addition to its use in renal transplantation protocols, daclizumab was included in the spectrum of immunosuppressive agents for gluco-corticoid-free immunosuppression administered in an islet cell transplantation protocol used for patients with type 1 diabetes mellitus that provided excellent meta-bolic control (Shapiro et al., 2000). In addition, we and our collaborators have shown that daclizumab (Human-ized anti-Tac) is of value in the therapy of select T cell mediated autoimmune disorders. In particular, the mAb provided effective treatment for noninfectious interme-diate and posterior uveitis in a clinical trial (Nussenblatt et al., 1999). Furthermore, daclizumab therapy of pa-tients with the neurological disease, HTLV-I-associated HAM/TSP, led to a reduction in HTLV-I viral load, a de-crease in the ex vivo spontaneous T cell proliferation of

peripheral blood mononuclear cells, and the stabiliza-tion or amelioration of the neurological disease (Lehky et al., 1998). Continuous mAb administration was re-quired to maintain the desired clinical effects.

IL-15/IL-15R-Directed Therapy for Autoimmune Disease and to Prevent Allograft Rejection

Although IL-2Ra-directed therapy has met with consid-erable success in the treatment of leukemia, select auto-immune disorders, and in the prevention of allograft rejection, approaches directed toward this receptor subunit have limitations. In particular, antibodies to IL-2Ra, the private receptor for IL-2, do not inhibit the actions of IL-15, a cytokine that does not bind to this subunit. Another limitation of IL-2Ra-directed therapy is that antibodies directed toward this receptor do not act on resting NK- or NK-T cells that express IL-2Rb and gc but not IL-2Ra. An additional limitation is suggested by our discussion above on the special functions of the IL-2/IL-2Ra system. In particular, inhibition of IL-2-medi-ated AICD by anti-IL-2R-directed therapy may prevent the generation of AICD-associated peripheral tolerance to both self and to transplantation antigens. The genera-tion and maintenance of such tolerance could be of value in the treatment of autoimmune disease and in the prevention of organ allograft rejection. Kirk and co-workers (Kirk et al., 1999) demonstrated that relatively short-term administration of an anti-CD40 ligand anti-body provided long-term protection against renal allo-graft rejection in nonhuman primates. However, the ad-dition of agents such as tacrolimous (FK506) and cyclosporin A that inhibit signaling through the T cell receptor and thereby inhibit IL-2 synthesis antagonized the long-term tolerogenic effect of the anti-CD40 ligand antibody (Kirk et al., 1999). In light of these observations, an evaluation should be made of anti-IL-2Ra monoclonal antibody therapy such as that used in organ (e.g., islet cell) transplantation for its potential to inhibit AICD and thereby to preclude the induction of the desired antigen-specific allograft tolerance.

Due to these limitations in IL-2 receptor-directed ther-apy, IL-15 receptor-directed therapy is being developed for use in organ transplantation protocols, for applica-tion to the treatment of autoimmune disorders as well as diseases caused by the retrovirus HTLV-I. Abnormali-ties of IL-15 expression have been reported in diverse inflammatory and neoplastic diseases (Waldmann and Tagaya, 1999). In particular, abnormally high levels of IL-15 transcription and translation were observed in HTLV-I-associated diseases such as adult T cell leuke-mia as well as the autoimmune disorder, tropical spastic paraparesis (TSP) (Azimi et al., 1999). The HTLV-I tax protein through a mechanism involving NFkB induced the expression of IL-15 and IL-15Ra. In addition, abnor-malities of IL-15 expression were described in inflamma-tory autoimmune disorders including rheumatoid arthri-tis, inflammatory bowel disease, multiple sclerosis, chronic liver disease, and pulmonary sarcoidosis. For example, McInnis and coworkers (McInnes et al., 1997) reported abnormalities of IL-15 in rheumatoid arthritis and suggested that IL-15 expression may precede that of TNFa and that IL-15 may be at the apex of a cytokine cascade that includes downstream IL-1, IL-6, GM-CSF, as well as a series of inflammatory chemokines including Mip1a, Mip1b, and IL-8. Other groups demonstrated IL-

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15 production by endothelial cells in rheumatoid tissues, showed that intraarticular injection of IL-15 led to T cell accumulation in rheumatoid arthritis synovial tissues en-grafted into SCID mice in vivo, and that such injections of IL-15 led to the recruitment of activated T cells into the synovial membrane, possibly contributing to the pathogenesis of the arthritis (Oppenheimer-Marks et al., 1998). On the basis of these observations, a number of new therapeutic approaches directed toward IL-15, its receptor, or to Jak3, a critical element in its signaling pathway, are being developed for use in the therapy of inflammatory autoimmune disorders. The administration of an IL-15 inhibitor, the soluble high-affinity IL-15Ra receptor chain, prevented the development of murine collagen-induced arthritis and inhibited allograft rejec-tion (Ruchatz et al., 1998). Furthermore, an IL-15 recep-tor antagonist produced by mutation of a glutamine resi-due within the C terminus of IL-15 to aspartic acid competitively inhibited IL-15-triggered cellular prolifera-tion (Kim et al., 1998). This IL-15 mutant markedly at-tenuated antigen-specific delayed hypersensitivity re-sponses in Balb/c mice and enhanced the acceptance of pancreatic islet cell allografts (Kim et al., 1998). Our own IL-15-directed therapeutic approaches have fo-cused on the IL-2Rb receptor subunit shared by IL-2 and IL-15 in an effort to yield more profound immuno-suppression than can be achieved by inhibition limited to the action of a single cytokine such as IL-2 or by an antibody directed toward a private receptor such as IL-2Ra (Tinubu et al., 1994; Waldmann and OShea, 1998). Our initial trials involved Mikb1, an antibody directed toward IL-2Rb that inhibits IL-15 action on T and NK cells. A humanized version of this antibody prolonged renal allograft survival in cynomolgus monkeys (Tinubu et al., 1994). In our initial clinical trial, we are evaluating Mikb1 in the therapy of patients with T cell type large granular lymphocytic leukemia associated with hemato-cytopenia. The monoclonal large granular lymphocytes (LGLs) involved in this disease express IL-2Rb and gc but not IL-2Ra (Tsudo et al., 1987) and respond to IL-15. Finally, as a substitute for the present IL-2/IL-2R-directed therapeutic agents, IL-15/IL-15R-directed ther-apy should be evaluated in clinical trials involving organ allografts in light of the reported success of this ap-proach in preclinical models (Tinubu et al., 1994; Kim et al., 1998). Such therapy focusing on IL-15 is supported in part by the desire to inhibit the stimulatory action normally played by IL-15 on activated T and NK cells. Furthermore, as discussed above, an objective of such therapy directed toward the IL-15/IL-15R system would be to interfere with the IL-15-mediated persistence of CD81 memory phenotype T cells and to eliminate the inhibitory action normally played by IL-15 on IL-2-medi-ated AICD. These agents that inhibit IL-15 action could be of value in other situations where self-tolerance is of value such as in the treatment of autoimmune diseases or in allograft protocols where the development of peripheral tolerance to the graft is desired.

The Use of IL-15 in the Therapy of Cancer and as a Component of Vaccines

IL-2 has been approved for use in the treatment of pa-tients with metastatic renal cell carcinoma or with meta-static melanoma. It has also been used as a component of vaccines for cancer. However, due to its pivotal role

in AICD it may lead to the death of T cells that recognize antigens expressed on the tumor cells. That is, these cells may interpret the tumor cells as self. Futhermore, the inhibition mediated by IL-2 on the survival of memory T cells directed toward the tumor is not desired. Thus, IL-15 with its inhibitory action on AICD and its stimula-tory role in the persistence of memory CD81 T cells may be superior to IL-2 in the treatment of cancer and as a component of vaccines directed toward cancer or infectious agents.

In conclusion, our emerging understanding of the IL-2/IL-2R and IL-15/IL-15R systems including the defini-tion of the actions that these cytokines share as well as those functions where their roles are distinct opens new possibilities for the development of more rational im-mune intervention that may be of value in the prevention of allograft rejection, in the treatment of lymphocytic leukemia/lymphoma, diseases associated with the ret-rovirus HTLV-I, as well as T cellmediated autoimmune disorders.

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