Interferon-Gamma, the Activated Macrophage, and Host Defense Against Microbial Challenge

BASIC REVIEW

Interferon-Gamma, the Activated Macrophage, and Host Defense Against

Microbial Challenge HENRY W. MURRAY, M.D.; New York, New York

Recent research on human macrophage activation has re-emphasized the critical role of the lymphokine-secreting T cell in converting quiescent macrophages to efficient microbicidal phagocytes. Interferon-gamma, a key lymphokine secreted by antigen-triggered T4+ helper cells, is capable of inducing the macrophage to act against a diverse group of microbial targets, in particular, intracellular pathogens. In animal models, treatment with recombinant interferon-gamma is beneficial in systemic intracellular infections, and inhibition of endogenous interferon-gamma activity impairs host resistance. Trials in patients with cancer, leprosy, and the acquired immunodeficiency syndrome (AIDS) have shown that interferon-gamma can activate the mononuclear phagocyte in humans. This research and the identification of patients whose T cells fail to produce interferon-gamma properly has set the stage for evaluating the role of macrophage-activating immunotherapy using interferon-gamma in various human infectious diseases.

[MeSH terms: acquired immunodeficiency syndrome; anti-infective agents; interferon type II; leukocytes, mononuclear; lymphokines; macrophage activation; macrophages; monocytes; neoplasms; phagocytes; recombinant proteins; T lymphocytes. Other indexing terms: extracellular pathogens; host defense; intracellular pathogens]

A L M O S T A CENTURY ago, Metchnikoff (1) introduced the concept of macrophage activation and suggested a potentially key role for the activated mononuclear phagocyte in defense against and recovery from microbial challenge. Sixty years later, Mackaness (2, 3) extended the work of other investigators (4) and developed the experimental framework in which macrophage activation has been shown to largely mediate the cellular immune response to intracellular pathogens (5) . At same time and in seemingly unrelated work, Wheelock (6) reported the presence of a new antiviral protein, subsequently termed "immune" (7, 8) or type II interferon, and now known as interferon-gamma. During the next two decades, the original observations of Mackaness and Wheelock were greatly amplified but remained unconnected. Between 1982 and 1983, however, a series of in-vitro studies provided clear evidence directly linking interferon-gamma with the two expressions of macrophage activation most relevant to host defense—enhanced antimicrobial activity (9-11) and augmented tumor cell killing (12-16).

Before the discovery of the specific relation among interferon-gamma, macrophage activation, and microbial killing (9-11, 17), abundant experimental data had accumulated to indicate that macrophage activation was T cell-dependent (4, 5) . Successful acquisition of in-vivo

resistance to infection caused by intracellular pathogens, for example, could be transferred only with sensitized (immune) lymphocytes (18, 19), later proved to be T cells (20-22). Moreover, T cell-deficient nude (athymic) mice were shown to be remarkably susceptible to, and for the most part unable to control, intracellular infections (23-26).

In addition, in the 1970s and 1980s, many laboratories successfully extended earlier in-vitro studies (4, 27-29) that had established that macrophage activation, as expressed by enhanced antimicrobial activity, was dependent on either sensitized lymphocytes (T cells) or their secretory products. In most (30) of the subsequent models of cellular immunity, T cells stimulated by previously encountered specific antigens or by nonspecific mitogens have been shown to release soluble products (lymphokines) (31) capable of inducing the quiescent macrophage to express augmented antimicrobial effects (4, 5) . Although these T cell-derived lymphokines are now known to comprise various factors that exert diverse im-munoregulatory actions, the original preparations were crude (uncharacterized) and collectively termed "macrophage activating factor" (32-34).

Recent advances, however, including the development of monoclonal antibodies and recombinant technology, have allowed investigators to refine their analysis of the immunologic basis of mononuclear phagocyte activation (17, 34). The clinical relevance of defining the key role that one specific T-cell product, interferon-gamma, plays in activation, and thus host defense, relates to the potential to therapeutically induce macrophage activation in humans. The capacity to pharmacologically activate the tissue macrophage or its precursor, the circulating blood monocyte, may prove useful and warrants evaluation in the management of selected patients with infections for which conventional therapy is not uniformly effective. Such patients would include those patients whose T cells fail to secrete interferon-gamma properly and who are infected with intra- or extracellular pathogens known to be susceptible to the interferon-gamma-stimulated mononuclear phagocyte.

Although interferon-gamma shows remarkably pleio-tropic activities (34-38), this review will be limited to interferon-gamma's role and effect in host defense as it relates to macrophage activation for enhanced activity against nonviral pathogens.

The Interferons

Leukocyte-derived interferon-alpha and fibroblast-de-rived interferon-beta were the first interferons to be characterized (36-38). These proteins were found to be re-

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leased by various cells after in-vitro viral infection, and once applied to other target cells, provided protection against subsequent viral challenge. There are now at least 13 different types of interferon-alpha and two distinct forms of interferon-beta known (39) . In 1965 Wheelock (6) showed a third type of interferon, interferon-gamma, secreted by human peripheral blood mononuclear cells in response to stimulation with the T-cell mitogen, phyto-hemagglutinin. Subsequently, it was shown that interferon-gamma was also produced by mononuclear cells in response to specific microbial antigens (40-43).

By definition, all three interferons showed the capacity to induce the antiviral state, but interferon-gamma proved to be clearly different from interferon-alpha and -beta in most other regards, including structure, cellular sources, stimuli that induced secretion, physicochemical properties, cell surface receptors, antiviral efficacy, and antiproliferative activity (34-38, 44). With the availability of pure recombinant interferon preparations, the differences between the immunologic actions of interferon-gamma and interferon-alpha and -beta have been magnified further (34, 35).

Native interferon-gamma is a pH 2-labile, highly basic heterogeneous glycoprotein (estimated molecular weight 40 000 to 70 000 daltons) which can be resolved into three monomelic forms of 25 000, 20 000, and 15 500 daltons (34, 36, 44). Interferon-gamma can aggregate to form dimers that may represent the biologically active form of the natural protein (44). Cloned recombinant interferon-gamma is not glycosylated, and has a predicted size of 17 000 daltons for the mature protein (44) .

Interferon-Gamma in Macrophage Activation In Vitro

Early studies (6, 7, 40-43) showed that stimulated human peripheral blood mononuclear cells readily released interferon-gamma into the culture supernatant. From concurrent work (29, 32, 33, 45-48), it was also clear that these same crude lymphocyte supernatants (lympho-kines) could modulate macrophage function and induce enhanced antimicrobial effects (27, 29). This latter activity was seen particularly for intracellular pathogens that otherwise entered and successfully replicated within unstimulated macrophages (4, 5) . Accurate identification of the active component(s) within these crude lympho-kines, however, awaited the development of monoclonal antibody probes (34, 35) and recombinant technology (49, 50).

A series of collaborative studies (9-11) used human monocyte-derived macrophages as effector cells and crude human lymphpkines, a monoclonal anti-interferon-gamma antibody prepared by Rubin and associates (51) , and pure recombinant interferon-gamma (49) as key reagents. In these experiments, lymphokine-induced macrophage activation for enhanced antimicrobial activity proved to be both interferon-gamma-dependent and inducible by interferon-gamma alone (9-11). T cell-derived lymphokines rich in interferon-gamma were incubated with an anti-human interferon-gamma monoclonal antibody that neutralizes only interferon-gamma (51) . Antibody treatment essentially removed all macrophage-

activating effects and eliminated the ability of both mitogen- and antigen-stimulated lymphokines to induce macrophages to kill or inhibit three diverse human intracellular pathogens, Toxoplasma gondii, Leishmania do-novani, and Chlamydia psittaci (9-11). In parallel, depletion of interferon-gamma also eliminated the ability of crude lymphokines to enhance the macrophage's capacity to release H2O2 (9, 10). The role of H2O2 as a microbicidal oxygen intermediate has been well established (52) , and augmented H2O2 production represents a consistent biochemical correlate of the activated state (53-55).

Equally important and in a fashion identical to crude lymphokines, subnanomolar amounts of recombinant interferon-gamma alone successfully induced macrophages to kill or inhibit T. gondii, L. donovani, and C. psittaci (9-11), and directly enhanced respiratory burst activity (H2O2 release) (9, 10). Stimulation with various other cytokines did not achieve macrophage activation (9-11, 56). Subsequent work (17) in which both human and murine mononuclear phagocytes and diverse microbial targets were examined, has greatly expanded the remarkable spectrum of both intra- and extracellular pathogens that are killed or inhibited by the interferon-gamma-acti-vated macrophage (Table 1).

Differential Microbial Susceptibility

Although the macrophage stimulated by interferon-gamma is broadly active (17) , its efficacy has not been tested against certain extracellular pathogens such as Pneumocystis carinii. Nor do all the intracellular pathogens listed in Table 1 show the same degree of in-vitro susceptibility. Thus, for example, while ingested T. gondii and L. donovani are killed by the interferon-gamma-acti-vated human monocyte-dervied macrophage (9, 10, 56-58), C. psittaci resists killing, but its replication is effectively inhibited (11, 59). In addition, Mycobacterium tuberculosis and M. avium-intracellulare have been singled out because of their apparent in-vitro resistance to the antimicrobial effects of the interferon-gamma-treated human macrophage (60, 61). While some microorganisms may be resistant to the macrophage stimulated by interferon-gamma, the results with these two mycobacteria may reflect strain-to-strain variations in susceptibility (62) or differences in laboratory models. The failure of the interferon-gamma-activated macrophage to act against certain strains of M. tuberculosis and M. avium-intracellulare is surprising in view of other in-vitro and in-vivo observations that indicate that host defense against mycobacteria is T cell-dependent (4, 22, 27, 63-67) and is likely to involve interferon-gamma (62, 68-80).

Macrophage Activation Unrelated to Interferon-Gamma

Some of the studies that have confirmed the key role of interferon-gamma in macrophage activation have also provided evidence that other factors can induce enhancement in antimicrobial and oxidative activity. Most of these cytokines are currently uncharacterized (81-86); however, tumor necrosis factor, a mononuclear phagocyte product, has been reported to induce human macro-

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Table 1. Intra- and Extracellular Nonviral Human Pathogens Susceptible to the Interferon-Gamma-Activated Monocyte or Macrophage In Vitro*

Category Intracellular Extracellular

Protozoa Toxoplasma gondii Entamoeba histolytica Leishmania Plasmodium falciparum

L. donovani L. mexicana L. major

Trypanosoma cruzi

Helminths Schistosoma mansoni

Bacteria Listeria monocytogenes Salmonella typhimurium Legionella pneumophilia Mycobacterium tuberculosis

Fungi Histoplasma capsulatum Blastomyces dermatiditis Candida albicans C. parapsilosis Cryptococcus neoformans

Chlamydia C. psittaci C. trachomatis

Rickettsia R. prowazekii R. coronii R. tsutsugamushi

* Adapted from Nathan (17). Role of interferon-gamma in human or mouse peritoneal macrophage activation judged by effects using recombinant interferon-gamma alone or reversal of lymphokine-induced activation by an anti-interferon-gamma antibody.

phages to kill intracellular Trypanosoma cruzi (87) and M. avium-intracellulare (61) but not T. gondii (56, 87). These data raise the possibility of relatively narrow-spectrum macrophage-activating factors derived from cells other than lymphocytes. The T-cell product, granulocyte-macrophage colony-stimulating factor, may also exert similarly narrow activity because it stimulates the killing of Leishmania (88, 89), but not T. gondii (56) .

Kinetics of Mononuclear Phagocyte Activation

The human monocyte-derived macrophage is a quiescent cell that usually requires at least 12 to 24 and up to 72 hours of in-vitro exposure to recombinant interferon-gamma before showing optimal expression of the activated state (9-11, 17, 58). For macrophages, the activated phenotype is a relatively transient phenomenon, and wanes within 2 to 3 days after removal of interferon-gamma (9, 10). In contrast, if the fresh peripheral blood monocyte, a cell already intrinsically active in antimicrobial and respiratory burst capacity (53, 55, 57, 59, 90), is treated with recombinant interferon-gamma, the results are quite different. Comparatively brief exposure (6 to 24 hours) to relatively low concentrations of recombinant interferon-gamma induces persistent activation for up to 5 to 7 days in the absence of further treatment (91, 92).

In some models (93), as little as 1 hour of exposure to recombinant interferon-gamma is sufficient to activate monocytes to show enhanced intracellular antimicrobial effects. Thus, in a focus of infection within the tissues associated with sensitized T cells (for example, a granuloma), the relatively slow activation of the parasitized resident macrophage might be effectively offset by the more rapid and longer-lasting activation of the influxing blood monocyte. The latter phagocyte has been shown to be particularly important in defense against intracellular

Listeria monocytogenes (94) . In some in-vitro systems, macrophages must be pre-

treated before challenge with rapidly dividing intracellular micro-organisms (T. gondii, C. psittaci) to show interferon-gamma's activating effects (11, 57, 95). However, recombinant interferon-gamma can also induce the killing of more slowly growing pathogens when applied after macrophage infection (91, 95), suggesting that therapy could activate infected cells and simultaneously prime adjacent macrophages destined to be but not yet challenged.

Activation of Other Host Defense Cells

In addition to human peripheral blood monocytes, human monocyte-derived macrophages, and resident mouse peritoneal macrophages (17) , the spectrum of host defense cells capable of responding to recombinant interferon-gamma with in-vitro antimicrobial activity has recently been expanded to include human and murine alveolar macrophages (96-98), human placental and peritoneal macrophages (58) , and murine hepatic macrophages (Kupffer cells) (99) . Although not usually considered to be host-defense cells in the traditional sense of the phagocytic leukocyte, human and murine fibroblasts (100-102), human endothelial (57, 102), epithelial, and parenchymal cells (103-105), and murine astrocytes (106) have also been shown to respond to recombinant interferon-gamma with intracellular microbicidal or microbistat-ic activity.

Antimicrobial Mechanisms of the Activated Macrophage

The mononuclear phagocyte's antimicrobial mechanisms are both oxygen- (respiratory burst-) dependent and oxygen-independent (107). Treatment of the resting macrophage with crude lymphokines markedly increases

Murray • Interferon-Gamma 5 9 7


the capacity to release toxic oxygen intermediates on subsequent triggering, and superoxide anion, H 2 0 2 , and hy-droxyl radical all appear to play primary roles in intracellular antimicrobial activity (52, 55, 57, 90, 107-109). Studies of oxidatively deficient mononuclear phagocytes from patients with chronic granulomatous disease and oxidatively inactive human fibroblasts, endothelial cells, and murine macrophages have also shown an additional respiratory burst-independent mechanism (55, 57, 59, 90, 108-111) that can be augmented by crude lymphokines (55, 57, 59, 84, 112, 113). Stimulation of the enzymatic degradation of extracellular tryptophan (100, 103, 114, 115) and limiting the availability of iron (116) may represent J of several potential oxygen-independent mechanisms. Current evidence (9, 10, 17, 56, 57, 59, 95, 96) suggests that the enhancement in oxygen-dependent and -independent activity achieved by lymphokines is largely interferon-gamma-dependent and can be induced by recombinant interferon-gamma alone. Thus, both the macrophage's basic antimicrobial mechanisms appear to be primarily, but probably not exclusively (81-89), regulated by interferon-gamma.

Other than the observation that human mononuclear phagocytes show surface receptors for interferon-gamma (117) that probably undergo recycling (118), there is currently little understanding of the plasma membrane or intracellular molecular events that culminate in interfer-on-gamma-induced macrophage activation. Interferon-gamma's ability to influence calcium fluxes (119) and enhance the activity of protein kinase C (120, 121) may both be relevant.

In-Vivo Macrophage Activation in Animal Models

Initial experiments in mice showed that interferon-gamma could also activate the macrophage in an in-vivo environment (95). Twenty-four hours after intraperitoneal treatment with recombinant murine interferon-gamma, peritoneal macrophages were vigorously activated and killed both intracellular T. gondii and L. donovani and released high levels of H2O2. In-vivo activation required a single injection of only nominal doses of interferon-gamma, and intramuscular and intravenous injection also readily activated macrophages in the peritoneal cavity (95). This latter observation and more recent findings (97) have confirmed interferon-gamma's ability to reach and stimulate the tissue macrophage in a distant anatomic compartment. If peritoneal or alveolar macrophages were examined at 48 to 72 hours rather than 24 hours after treatment, however, little evidence of the activated phenotype was seen (95, 97). Therefore, two or three injections of recombinant interferon-gamma per week, or perhaps less frequent but more prolonged infusions (92) , may be sufficient to maintain the tissue macrophage in the activated state.

The demonstration that interferon-gamma can enhance in-vivo host defense against systemic intracellular infections thought to need activated macrophages for successful control has been particularly relevant to potential immunotherapy. Thus far, treatment with recombinant interferon-gamma prophylactically or after estab

lished infection has achieved various degrees of beneficial effects in models of infections caused by L. monocytogenes (122), T. gondii (123), M. bovis (75) , M. tuberculosis (76) , M. intracellular (74) , L. donovani (25) , Salmonella typhimurium (124), and Francisella tularensis (125). Prophylactic therapy with recombinant interferon-gamma has also proven active against the exoerythro-cytic stage of Plasmodium in experimental malaria, presumably by activating the parenchymal hepatocyte (126, 127).

Additional animal studies have indicated that exoge-nously administered interferon-gamma can also induce other effects potentially beneficial to host antimicrobial activity. These effects include increasing the tissue expression of class I and II major histocompatibility complex antigens (128-131), stimulation of helper T-cell function with enhanced interleukin-2 production (132), and augmentation of vaccine immunogenicity (133).

Role of Endogenous Interferon-Gamma

Buchmeier and Schreiber (134) have recently provided evidence that endogenously generated interferon-gamma plays a key role in macrophage activation and defense against intracellular pathogens. Mice injected once with a monoclonal anti-murine interferon-gamma antibody at the time of infection with L. monocytogenes failed to clear a sublethal challenge inoculum, and one third of antibody-treated mice but none of the control mice died (134). Repeated injections of the same anti-interferon-gamma antibody (134) also impaired the capacity of mice to acquire resistance to and control the intracellular visceral replication of L. donovani (135). Similar results have been reported for mice infected with Rickettsia co-norii (136).

For both L. monocytogenes and L. donovani, effective host defense is primarily T cell-dependent, activated mac-rophage-mediated (5, 25, 134), and correlates with the capacity of T cells to secrete antigen-induced interferon-gamma (25, 134). Although interferon-gamma has been detected in the circulation of mice with systemic intracellular infections (7, 137-140), the effect of anti-interferon-gamma antibody treatment on infections caused by these representative pathogens implies a pivotal role for endogenous interferon-gamma in macrophage activation in vivo (134-136). However, treatment with antibody to interferon-gamma did not cause all L. monocytogenes- or R. co/20/7/-challenged mice to die (134, 136) or prevent L. donovani-infected mice from eventually gaining some control over visceral parasite burdens (135). Thus, the presence of interferon-gamma-independent T-cell mechanisms or perhaps host defense responses entirely independent of T cells appears likely (24).

Sources and Mechanisms of Interferon-Gamma

In response to in-vitro stimulation with nonspecific mitogens or interleukin-2, human T4+ (helper) cells, T8 + (suppressor) cells, and natural killer cells can be induced to secrete interferon-gamma (141-149). However, it is mainly the T4+ cell obtained from peripheral blood or serous cavities that produces interferon-gamma after ex-



posure to a previously encountered (specific), soluble microbial antigen (149-151); hence, the critical role of the sensitized T4+ cell in macrophage activation. Not surprisingly, antigen-stimulated interferon-gamma secretion has proved to be a sensitive and specific in-vitro marker of T4+ cell immunocompetence in diseases such as the acquired immunodeficiency syndrome (AIDS) (152-155).

Once triggered by either mitogen or specific antigen, the production of interferon-gamma by activated T cells starts rapidly. After 6 hours of stimulation, interferon-gamma mRNA is fully expressed in human T cells (156) and the release of interferon-gamma can be detected (149). Peak interferon-gamma levels are usually present by 48 to 72 hours (149); however, in-vitro production may continue for as long as 8 days (41-43, 157, 158).

The molecular mechanisms that culminate in the generation of mitogen- or antigen-stimulated interferon-gamma are complex and at best only partially defined. These mechanisms are likely to involve the accessory cell activity of mononuclear phagocytes or dendritic cells that process and present antigen, release interleukin-1, and express the class II major histocompatibility complex products required for T-cell activation (43, 144, 157, 159-164); T-cell production of interleukin-2 (144, 149, 157, 164-168); and interleukin-2 receptor expression on activated T cells (149, 167-170). Once produced, interleukin-2 can directly induce the expression of T cell interferon-gamma mRNA (171), and stimulate both T4+ and T8 + cells to secrete interferon-gamma (144, 149). However, only T 4 + cells are capable of generating interleukin-2 in response to specific soluble antigen (149, 172). Recent evidence (149) suggests that selected microbial antigens may also stimulate T4+ cell interferon-gamma production by an auxiliary mechanism that is largely independent of interleukin-2 and its receptor. T-cell proliferation is not necessarily required for interferon-gamma generation (37) .

The immune circuitry that culminates in interferon-gamma secretion also appears to contain several intertwined amplifying mechanisms. Interferon-gamma can directly feed back to enhance accessory cell function by inducing the expression of class II major histocompatibility complex molecules (173-175), priming or stimulating macrophages to release interleukin-1 (175-177), and by augmenting antigen presentation (178). Further, interferon-gamma may enhance interleukin-2 production or increase responsiveness to interleukin-2 by inducing T cells to show interleukin-2 receptors (179-181). Interleukin-2 also augments the expression of its own receptor (167), and together with interleukin-1 (182), can act synergistically to stimulate interferon-gamma secretion (164). Various nonimmune factors may also modulate interferon-gamma production at least in vitro: zinc and angiotensin II stimulate secretion (183, 184) whereas 1,25 -dihydroxyvitamin D3 and endogenous opiates can suppress secretion (156, 185-187).

In-Situ Production of Interferon-Gamma

Until recently, interferon-gamma was considered an

exclusive product of stimulated lymphocytes. However, it now appears that in-vitro-triggered alveolar macrophages from healthy volunteers (188) and unstimulated alveolar macrophages from patients with active pulmonary sarcoidosis (189, 190) can generate interferon-gamma in culture. An inflammatory disorder characterized by increased numbers and exuberant activity of T4+ cells (189, 190), sarcoidosis was one of the first diseases in which interferon-^ nma was shown in situ in granulomatous areas of lung and lymph node (191). In humans, tissue interferon-gamma has also been shown immunocy-tochemically in five other inflammatory disorders—tuberculosis (lymph nodes, lung) (191), rheumatoid arthritis (synovium) (192), polymyositis (muscle) (193), herpetic infections (skin vesicles) (194), and subacute thyroiditis (infiltrating lymphoid cells) (195).

Biologically active interferon-gamma has also been seen in vesicle fluid in patients with psoriasis (196) and Herpes simplex infection (197), in the serum of patients with P. falciparum malaria (198), in the serum and synovial fluid of patients with various autoimmune diseases (199-201), and in the cerebrospinal fluid of patients with viral encephalitis, meningitis (202), and multiple sclerosis (200). Treatment of patients with multiple sclerosis with interferon-gamma may precipitate clinical exacerbations (203). Interferon-gamma is seldom seen in the serum of healthy persons (198, 199).

Diseases Associated With Deficient Interferon-Gamma DEFECTS A T BIRTH OR INHERITED DISORDERS

A congenital defect resulting in the isolated failure of T cells to produce interferon-gamma has not been described. However, mitogen-stimulated T cells from healthy newborns secrete considerably less interferon-gamma than do cells from adults, and in some instances, neonatal cells fail to generate any detectable interferon-gamma (204). Multiple mechanisms appear t-; underlie this presumably transient and self-limited but complex defect (204-206). Children and adults with primary immunodeficiency states including IgA deficiency, hypogammaglobulinemia, ataxia-telangiectasia, hyper-IgM and -IgE syndromes, and common variable immunodeficiency are subject to infections and show impaired mitogen-stimulated interferon-gamma generation in vitro (207, 208). A similar defect has also been described in patients with Down syndrome (209) and retinitis pigmentosa (210). Children with congenital infections caused by rubella virus and cytomegalovirus show defective interferon-gamma production in response to specific viral antigen (211, 212).

ACQUIRED DEFECTS IN MITOGEN-STIMULATED

INTERFERON-GAMMA PRODUCTION

There are many examples of acquired defects in interferon-gamma secretion (Table 2) that in some, but not all, instances correlate with increased vulnerability to opportunistic infections. The literature concerning acquired defects in interferon-gamma production is, however, difficult to analyze because of the diverse group of stimuli (primarily nonspecific mitogens) that have been used to



Table 2. Disorders or States Associated with Acquired Defects In In-Vitro Interferon-gamma Production

Impaired T Cell Response to:

I. Mitogen (no an tigen tested) Systemic lupus erythematosus Rheumatoid arthritis Psoriasis Multiple sclerosis Fulminant viral hepatitis Chronic hepatitis B virus infection Central nervous system disorders* Chronic lymphocytic leukemia Acute lymphocytic leukemia Renal transplantation Trauma Hodgkin disease in remission Condyloma accuminata

II. Specific Microbial Antigen (no mitogen tested)f t Malaria Orolabial Herpes simplex virus infection Cytomegalovirus infection Cardiac transplantation Lymphoma

III. Mitogen and Specific Microbial Antigen J Bone marrow transplantation Acquired immunodeficiency syndrome ( A I D S ) /

AIDS-related complex IV. Specific Antigen from Infecting Pathogen Only§

Leprosy Leishmaniasis Tuberculosis Filariasis

* Including intracranial tumors, post-craniotomy state, myasthenia gravis, Alzheimer disease, Huntington chorea, stroke, and viral meningoencephalitis (218, 219).

t Specific microbial antigen = previously encountered antigen as judged by positive serologic testing or confirmed microbiologic diagnosis.

X One specific antigen tested for cells from patients with malaria, Herpes simplex infection, cytomegalovirus infection, and bone marrow transplantation. Multiple specific antigens used to test patients with cardiac transplantation, lymphoma, and the acquired immunodeficiency syndrome (AIDS).

§ Interferon-gamma production in response to mitogen and other specific antigens generally intact.

test patients' T cells in vitro. Natural killer, T4+, and T8+ cells can all secrete interferon-gamma in response to mitogens (141-149); thus, normal mitogen-induced interferon-gamma production can still be seen despite profound abnormalities in responses to immunologically relevant specific antigens that need functionally intact T4+ cells (149-151). The best example of such a state is seen in patients with AIDS (152-155).

However, the failure to respond to several T-cell mitogens with interferon-gamma secretion presumably signals a striking defect in the mechanisms of activation or the secretory activity of T4+, T8+, and natural killer cells. Such a defect in in-vitro responsiveness to one or more mitogenic stimuli has been reported in a variable proportion of patients with the disorders listed in group I of Table 2 (213-229). However, interpretation of these data is difficult because mononuclear cells from some of these patients respond normally to certain mitogens, and antigen-induced responses have not been studied. In addition, with the exception of patients with renal transplants and patients with lymphocytic leukemia, patients with the disorders in group I of Table 2, as well as adults with retinitis pigmentosa (210), are not known to be intrinsi

cally susceptible to recurrent or opportunistic infections. Therefore, the clinical implications of defective mitogen-stimulated interferon-gamma production remain to be clarified.

ACQUIRED DEFECTS IN ANTIGEN-STIMULATED

INTERFERON-GAMMA PRODUCTION

The acquired defects in antigen-induced interferon-gamma production can be divided into two categories— defects resulting from a generalized failure of T4+ cells to respond to specific soluble antigenic stimuli, and defects resulting from the inability of T4+ cells to respond to one selected antigen (Table 2) .

Global T4+ cell defects can be associated with neoplastic diseases that are intrinsically immunocompromising (230, 231); iatrogenic immunosuppression induced by radiotherapy, cytotoxic chemotherapy, and probably anti-T-cell agents such as cyclosporin A (226, 230-234); or any state that directly destroys the T4+ cell or impairs its activation or secretory function (for example, AIDS) (152-155). The capacity of immunosuppressive drugs such as cyclosporin A (235-237), corticosteroids (167, 237-239), and antimetabolites (238) to inhibit mitogen-stimulated interferon-gamma production has been well established and correlates with suppressed mitogen-induced interferon-gamma generation in many, but not all, renal and bone marrow transplant recipients and treated patients with lymphoma and leukemia (221, 224-226, 228, 234, 240, 241). Antigen-triggered interferon-gamma secretion is likely to be abnormal in these patient populations as well (230-234). However, the effect of corticosteroids (201, 213, 225, 226, 237-239) and other immunosuppressive agents on interferon-gamma production has been variable. Antigen-induced interferon-gamma secretion has not been formally studied in vitro with such agents, and cells from patients receiving immunosuppressive treatments have not been examined systematically for responsiveness to specific antigens.

Theoretically, any disease or agent that selectively impairs one or more of the key steps leading up to T-cell activation (accessory cell function, interleukin-1 production, interleukin-2 secretion, interleukin-2 receptor expression) could result in the failure to produce interferon-gamma in response to all specific microbial antigens.

In contrast to the disorders associated with a global deficit in T4+ cell responsiveness to antigen, there are several examples of infectious diseases in which the in-vitro defect in antigen-induced interferon-gamma production appears to be limited to the failure to respond to the infecting pathogen alone. Thus, peripheral blood mononuclear cells from certain otherwise healthy patients with malaria (242), recurrent H. simplex lesions (243), and cytomegalovirus infection (212) produce low or undetectable levels of interferon-gamma in response to the specific microbial antigen.

Cells from patients with lepromatous leprosy (69, 70), severe cutaneous and visceral leishmaniasis (244-246), tuberculosis (71, 72), and filariasis (microfilaremic state) (247) largely fail to respond to M. leprae, leishmanial, mycobacterial, or filarial antigens, respectively, but



typically generate interferon-gamma normally after stimulation with mitogens or other microbial antigens (group IV, Table 2) . This state clearly defines a highly restricted, antigen-specific defect and in turn correlates with a lack of generalized susceptibility to opportunistic pathogens in such patients. Moreover, after treatment and clinical improvement in leishmaniasis (244-246), for example, and perhaps in tuberculosis (71) , interferon-gamma production emerges in response to the specific antigen to which the patients' T cells originally failed to react. It is not yet known if similar events take place in tissue foci of infection, nor have the mechanism(s) underlying this reversible hyporesponsiveness to one specific antigen been clarified. Soluble suppressor factors or suppressor cells may be involved (248). In contrast, T cells from patients with better-controlled manifestations of these same infections (tuberculoid leprosy [69, 70] , mucocutaneous leishmaniasis [245], and filarial elephantiasis [247]) readily secrete interferon-gamma in response to specific microbial antigen.

Activation of Mononuclear Phagocytes by Interferon-Gamma

Recent studies in patients with cancer, leprosy, and AIDS have shown that exogenously administered recombinant interferon-gamma can also induce mononuclear phagocyte activation in humans. Nathan and colleagues (249) reported that after 6-hour intravenous infusions of recombinant interferon-gamma (100 to 1000 jixg/M2

body surface), blood monocytes from 11 of 13 patients with cancer showed evidence of activation as judged by enhanced H2O2 release in vitro. In a subsequent study, Nathan and associates (73) also showed that the oxidative activity of circulating monocytes from patients with lepromatous leprosy was persistently augmented for up to 2 weeks after intradermal or intramuscular injections of as little as 1 to 10 jutg (less than 10 u,g/M2) of recombinant interferon-gamma. Intralesional injections of recombinant interferon-gamma in these patients markedly enhanced dermal and epidermal cell class II major histocompatibility complex antigen (HLA-DR) expression, provoked a histologic response resembling a de-layed-type hypersensitivity reaction, and more importantly, induced local anti-Af. leprae activity (73) .

In patients with cancer, 250 to 500 f ig/M2 of recombinant interferon-gamma given daily by 6-hour intravenous infusion or by intramuscular injection enhanced the cytotoxicity of blood monocytes towards allogenic tumor cell targets in vitro (250). Intramuscular and subcutaneous injections of 10 to 100 f ig/M2 of recombinant interferon-gamma given daily or every other day have also resulted in monocyte activation in patients with cancer as judged by augmented in-vitro release of H2O2 (251).

In patients with AIDS, twice-weekly 2-hour intravenous infusions of recombinant interferon-gamma (700 to 3000 fxg/M2) did not enhance monocyte oxidative activity (superoxide anion release) (252); however, opposite results indicating monocyte activation have been reported in other studies (92, 253). In one trial (92), patients with AIDS with previous opportunistic infections received four once-weekly 24-hour continuous infusions of

30 or 500 f ig/M2 of recombinant interferon-gamma. Blood monocytes obtained after both high- and low-dose infusion remained persistently activated for up to 5 days in vitro, and showed clear increases in H202-releasing capacity and in the ability to act against intracellular T. gondii and L. donovani (92). One patient with AIDS relapsed with cryptococcal meningitis after his first infusion of 500 jxg/M2 of recombinant interferon-gamma (92) , perhaps reflecting poor penetration of interferon-gamma into cerebrospinal fluid (203) or the in-vitro observation that the activated macrophage inhibits but does not effectively kill Cryptococcus neoformans (254).

In other AIDS trials, treatment with up to 1000 jmg/ M2 of interferon-gamma increased natural killer cell activity, but had no apparent effect on established cytomegalovirus infection (253). In patients treated with thrice-weekly infusions of 10 to 1000 /xg/M2, monocyte expression of class II major histocompatibility complex antigen was enhanced; however, P. carinii pneumonia developed in three patients during the first week of therapy and in one who received low-dose recombinant interferon-gamma (10 jug/M2) (255). Although deficient T-cell function clearly predisposes patients to P. carinii and cytomegalovirus infection (5) , it is not yet known if interferon-gamma or the activated macrophage (256) play important host defense roles against these particular pathogens. Other positive immunologic responses associated with recombinant interferon-gamma treatment in patients with AIDS have included examples of conversion to reactive skin tests (257) and enhanced T-cell function including increased lymphokine generation (257, 258).

Other Immunomodulatory Effects

Data from the preceding clinical trials as well as other reports have also indicated that recombinant interferon-gamma can induce various other potentially relevant alterations in in-vivo immunoregulatory activities that had previously been documented only in vitro. These effects in patients with cancer, AIDS, multiple sclerosis, and leprosy have included enhancement or increases in mononuclear cell expression of class II major histocompatibility complex antigens (251, 259-262), natural killer cell number and cytotoxicity (251, 260-262), T4:T8 cell ratio (261), lymphocyte proliferation (262), monocyte Fc receptor expression (251), 02 microglobulin levels (263, 264) (presumably reflecting augmented class I major histocompatibility complex antigen expression) (265), and serum lysozyme levels (260). The latter may indicate an effect of recombinant interferon-gamma on the secretory activity of mononuclear phagocytes (266). Intradermal injections can also provoke the local influx of T4+ cells and monocytes (267).

Although not yet tested using cells from patients who have received treatment, it is worth noting that recombinant interferon-gamma can exert still other immunoregulatory activities in vitro that may also be involved in host defense in vivo—priming of mononuclear phagocytes to release and act synergistically with tumor necrosis factor (268-272), induction of secretion of colony stimulating

Murray • Interferon-Gamma 601


factors by T4+ cells (273), inhibition of suppressor T-cell activity (274) and monocyte release of potentially suppressive prostaglandins (275), augmentation of polymorphonuclear leukocyte (269, 276, 277) and B-cell function (278-280), complement activation (281, 282), generation of activated killer T cells (283), inhibition of monocyte migration (284), and stimulation of monocyte antibody-dependent cellular cytotoxicity (175), multinucleated giant cell formation (285), and interleukin-2 receptor activity (286, 287). The latter effect may permit monocytes to subsequently respond to interleukin-2 with increased release of the antimicrobial oxygen intermediate, H 2 0 2 (287).

In-Vivo Monocyte Activation and Interferon-Gamma Pharmacokinetics

After intravenous bolus injections, recombinant interferon-gamma is cleared rapidly from the serum in a mo-noexponential fashion with a half-life of 30 minutes (288). After intramuscular or subcutaneous injection, serum levels peak at 6 to 13 hours, and the serum half-life is prolonged to 3.5 to 7.5 hours (261, 288). During continuous intravenous infusions, serum levels increase for up to 6 hours and thereafter plateau (92, 263), but rapidly disappear within 1 to 2 hours of completing an infusion (263, 289).

The capacity of recombinant interferon-gamma to activate the blood monocyte does not, however, appear to correlate with either dose or serum level, and also varies depending on the in-vitro assay used to detect activation (73, 92, 249, 263, 264, 288, 289). For example, in patients treated with 30 or 500 fxg/M2 by 24-hour infusion, mean peak serum levels differed by 10-fold but were low (1.8 compared with 18.7 U /mL) ; however, the degree of monocyte activation for antimicrobial and oxidative activity was nevertheless comparable (92). In patients with leprosy, three daily intradermal injections of as little as 1 to 10 jmg of recombinant interferon-gamma (less than 1 to 10 jxg/M2) did not achieve detectable serum levels but induced prolonged activation of the circulating blood monocyte (73). Thus, in humans, we do not as yet know how little interferon-gamma is required to successfully and persistently activate the mononuclear phagocyte in vivo. High doses of exogenous recombinant interferon-gamma, however, may suppress monocyte function (250, 252).

Adverse Reactions The adverse reactions associated with recombinant in

terferon-gamma administration are similar to those seen after injection of interferon-alpha (290). Fever, fatigue, chills, myalgias, and headache are common at virtually any dose greater than 10 jxg/M2, can be dose-limiting at 500 /xg/M2 or greater (260, 263, 264, 288, 289), but may be blunted by pretreatment with antipyretics or diphenhydramine (92, 263). Isolated untoward events involving virtually all organ systems have occurred after both high-and low-dose therapy (260, 263, 264, 288, 289); however, clinically meaningful laboratory toxicity has not been frequent. Increases in hepatic transaminases (260, 263,

264, 288, 289), hypertriglyceridemia (291) and granulocytopenia (260, 288, 289) may occur, but resolve with discontinuation of treatment. Serious secondary bacterial infections have not been encountered, and granulocytopenia is not necessarily considered a dose-limiting toxicity (260). Of several hundred patients tested, none has developed neutralizing antibodies to interferon-gamma (92, 289).

Interferon-Gamma as Macrophage-Activating Immunotherapy Taken together, the results of the preceding trials indi

cate that interferon-gamma by itself can activate the human mononuclear phagocyte in vivo, and provide the rationale for determining the optimal dose, route, and administration schedule required for recombinant interferon-gamma to effectively achieve host defense cell activation in humans. The observations reviewed here should also provide the impetus for additional studies to define the spectrum of the infectious diseases associated with deficient T4+-cell production of antigen-stimulated interferon-gamma that might therefore respond to monomole-cular immunoreplacement therapy.

At the same time, this work has also raised many pertinent questions that can only be addressed by more experience with interferon-gamma. Future studies in humans should be directed at clinically relevant issues: defining the capacity of interferon-gamma to successfully activate the tissue macrophage; determining if immunotherapy with one molecule can benefit patients with T4+-cell defects; evaluating the efficacy of combining interferon-gamma with currently available but not uniformly effective antibiotic therapy, especially when standard therapy is prolonged or potentially toxic (for example, in infections caused by fungi, protozoa [292, 293] , mycobacteria, or perhaps the AIDS virus [294-296]); and determining if interferon-gamma should be administered with interleukin-2 or one or more of the other cytokines normally generated during the intact cellular immune response.

Addendum In addition to enhancing the oxygen-independent antimicro

bial activity of monocytes from patients with classic X-linked chronic granulomatous disease (CGD) (10, 57, 59), interferon-gamma has recently been shown to up-regulate expression of the X chromosome CGD gene resulting in two- to eightfold increases in vitro in superoxide anion production by granulocytes and monocytes from individuals with a less severe (variant) form of the disease (297). This observation suggests a new application for interferon-gamma as a potential corrective and therapeutic agent for a congenital disease manifested by recurrent infections. Preliminary results from an interferon-gamma trial now being carried out in CGD patients appear promising (J. Gallin. Personal communication).

ACKNOWLEDGMENTS: The author thanks Drs. Carl F. Nathan and John J. Stern for their reviews and suggestions for this manuscript.

Grant support: US Public Health Service (NIH) grants AI 21510 and AI 16963.

• Requests for reprints should be addressed to Henry W. Murray, M.D.; Room A-423, Cornell University Medical College, 1300 York Avenue; New York, New York 10021.

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Interferon-Gamma, the Activated Macrophage, and Host Defense Against Microbial Challenge