key: cord-0009205-364r7luy authors: Virelizier, J.-L. title: Interferons as cytokines regulating leukocyte functions in vivo date: 2007-10-14 journal: Ann Inst Pasteur Immunol DOI: 10.1016/s0769-2625(85)80078-7 sha: 103a32be6095ad8121a4ec33be16f9f176cd3507 doc_id: 9205 cord_uid: 364r7luy nan there seems to be no decisive demonstration that IFN have an immunoregulatory role in vivo, despite compelling convergence of indirect evidence in both man and experimental animals. Our own bias, however, is that the answer is positive, and we base this semi-rational feeling on the following arguments. The first argument is that IFN has at least one role that has been demonstrated in vivo, and that is its participation in host defence against viruses. The finding that IFN administration in experimental animals may provide some protection against virus infection was not entirely convincing, since it did not tell about the role of endogenous IFN in recovery. Decisive evidence has come from experiments using specific antibody to IFN-~ and -~ able to neutralize endogenously produced IFN molecules. The pioneering work by B. Fauconnier [1] provided encouraging evidence, and work by I. Gresser and his colleagues [2] has shown conclusively that administration of an antiserum to mouse IFN-~/~ enhanced viral replication and potentiated the disease induced by encephalomyocarditis, herpes simplex, Moloney sarcoma, vesicular stomatitis and Newcastle disease viruses. Using the same approach, we have shown that early IFN production has a critical role in the genetically controlled resistance to mouse hepatitis virus [3]. However, whereas this type of work demonstrates an important role for IFN in vivo, it does not elucidate whether endogenous IFN protects against virus infection directly through its antiviral properties or indirectly through its ability to modify the functions of immunocompetent cells. A second argument comes from the observation that IFN administration in patients exerts a series of effects that indicate a modification of leukocyte functions. Thus, repeated injections of leukocyte IFN cause reversible lymphopaenia and bone marrow hypoplasia [4] , and this is likely to be due to the well documented cytostatic effects of IFN on bone marrow precursor cells [5] . Similarly, IFN adminis-tration is frequently pyrogenic in patients, even when recombinant molecules are used [4] . This is reminiscent of our observation that incubation with ~-or ~-IFN of human monocytes increases the secretory potential of interleukin-1, a molecule which appears to be identical to endogenous pyrogen [6] . Clear evidence that IFN administration enhances natural killer (NK) activity has been obtained in both mice [7] and man [8] . Altogether, these observations indicate that exogenous IFN can manipulate some functions of leukocytes, but this does not necessarily imply a role of naturally produced interferons in immunoregulation. The immunological role of endogenous IFN secretion is certainly a key point of discussion in the present debate. In this field, the most telling evidence should come from the observation that an immunological disorder may result from defective production of IFN, as is seen in some inbred mouse strains or in humans with a (( selective ), defect of secretion of one or more IFN species. In the mouse, the pattern of inbred strains with low IFN production varies according to the inducer used and the IFN species considered. It is interesting, however, to compare the genetics of IFN-7 production with that of virus-induced (~/~) IFN. Some common features appear, since BALB/c mice appear to be low producers and C57BL/6 high producers, not only for IFN-7 [9] , but also for IFN production after stimulation with Newcastle disease virus (If-1 locus) mouse mammary tumour virus (If-2 locus) and Sendai virus (If-3 and If-4 loci) [10] . A striking correlation can be found between IFN production and the ability of these two mouse strains to cope with intracellular microorganisms. Thus BALB/c mice, apart from being low producers of both virusinduced and IFN-u are opposed to C57BL mice by their increased susceptibility to many infections including listeriosis [11] and herpes simplex virus infection [12] . This is reminiscent of the known macrophage-activatingfactor (MAF) effects of interferons in vitro, and suggests that impairment in the production of the two main species of leukocyte IFN (~ and -~) leads to defective activation of the reticulo-endothelial system with a secondary defect of immunity to a range of intracellular microorganisms. In the human, selective defects of IFN production clearly correlate with secondary immunological abnormalities which can be reversed by IFN therapy. In normal human neonates, susceptibility to infections with both viruses and intracellular microorganisms is enhanced, and this implies that T-cell immunity is impaired. No major T-cell abnormality can be substantiated, however, except for a profound defect in IFN-u secretion [13] . This is due to a special type of immunological dysregulation rather than an intrinsic defect and is associated with an increased sensitivity of IFN secretion to the suppressive effects of prostaglandins-E [14] . The relatively selective defect of at this age of life may be envisaged as a major cause of immunological dysfunction, since correction by IFN of two associated abnormalities, namely low NK activity [15] and low HLA-DR expression [16] , suggest that they are consequences rather than causes of the defect in IFN-u secretion. In human neonates, the defective IFN concerns only IFN-7 secretion, since secretion of I'FN-~ appears to be normal. Observations in the mouse, as discussed above, suggest that defective secretion of both types of IFN of leukocyte origin (~ and y) leads to severe impairment of the host defence against a range of infections with intracellular microorganisms. For the past 10 years, we have been investigating the functioning of the IFN .system in patients with constitutional immune disorders. Apart from a complete IFN-7 defect in patients without T lymphocytes, as expected in the absence of any T-cell function, two main types of ~(selective ~ defects of IFN secretion, contrasting with the normal character of other immunological functions tested, have been observed [17] . One is the inability of T cells to proliferate and to produce IFN-7 in response to the antigens of the intra-cellular microorganism causing persistent infection, such as BCG or salmonella. It is known that immunity against the intracellular (intra-monocyte) microorganism is based upon specific induction of lymphokines with MAF activities, able to activate macrophages for increased destruction of the microorganism. IFN-T is able to activate monocytes for interleukin-1 secretion [18] and antimicrobial immunity [19] . Whatever the exact cause of this acquired T-cell unresponsiveness to persistent microorganisms, the lack of IFN-7 (and thus of MAF) secretion appears to be critical in the persistence of the microorganism in macrophages. Since all IFN species show MAF activities, we have treated some of these patients with IFN-~r and have obtained a striking regression of infections, as described previously [20] . The second situation is characterized by a selective defect of both IFN-~ induced by co-culture of leukocytes with lymphoblastoid cell lines and IFN-u induced by mitogens and antigens. This parallel defect contrasts with normal immune functions (antibody production, delayed hypersensitivity, T-cell markers and proliferation) and is associated with frequent, severe and persistent infections with both viruses (such as Epstein-Barr virus, adenovirus or coronavirus) and bacterial infections [17] . In such children, administration of IFN-~ was able to reverse a secondary defect of NK activity and permitted better control of infections [20] . Such observations, although made in rare patients, do indicate an immunoregulatory role for IFN in vivo. Better still, the association of a selection defect of 7-and ~-IFN secretion and a permanent, secondary defect of NK activity is compatible with the hypothesis that endogenous secretion of leukocyte interferons participates in the maintenance of a basic level (homeostasis) of activation of cells of the immune system, including NK cells and macrophages. It should be stressed again that none of the above listed observations constitutes definitive evidence that inter-ferons participate in the regulation of the immune system. Yet this idea is so powerful and irresistible, even if not yet demonstrated, that it should prompt further research in this area. As one great French biologist used to write (( Aimer une idSe, c'est l'aimer un peu plus qu'on ne devrait )) (Jean Rostand, (c Carnet d'un biologiste ))). As far as the therapeutic implications of the hypothesis are concerned, another sentence from the same scientist applies: (( Attendre d'en savoir assez pour agir en toute lumi~re, c'est se condamner h l'inaction )) (Jean Rostand, (( In-quiStudes d'un biologiste ))). [1] FAUCONNIER, B., Interferon: pharmacokinetics and toxicity Influence of interferon preparations on the proliferative capacity of human and mouse bone marrow cells in vitro Interferons as macrophageactivating factors. --II. Enhanced secretion of interleukin-1 by lipopolysaccharide-stimulated human monocytes Enhanced NK cell activity in mice injected with interferon and interferon inducers Induction and kinetics of natural killer cells in humans following interferon therapy Murine genotype influences the in vitro production of y (immune) interferon Considerations on mouse genes influencing interferon production and action, in (( Interferon I ), (Gresser I.) (p Resistance and susceptibility of mice to bacterial infection: genetics of listeriosis In vitro production of immune interferon by spleen cells of mice immunized with herpes simplex virus Defective IFN`( production in the human neonate.-I. Dysregulation rather than intrinsic abnormality Defective IFN~ production in the human neonate. --II. Role of increased sensitivity to the suppressive effects of prostaglandin E Human newborns are defcient in natural killer activity Cloned human interferon-,(, but not interferon-~ or -9 induces expression of HLA-DR determinants by fetal monocytes and myeloid leukemic cell lines Les d6ficits de production d'interf6rou chez l'enfant Interferon as macrophage-activating-factors. --III. Preferential effects of interferon `( on the interleukin 1 secretory potential of fresh or aged human monocytes Identification of IFNy as the lymphokin that activates human monocyte oxidative metabolism and antimicrobial activity Interferon administration as an immunoregulatory and antimicrobial treatment in children with defective interferon secretion, in , Primary immunodefieieneies As stated in the question asked by Dr De Maeyer, interferons appear to be able to modulate many different immune responses [41 . The bulk of these studies have been performed by determining the effects of exogenously added interferons on tissue culture systems and on animals [4] . However, there is a possibility that this myriad of immunological effects of the interferons may just be artifactual and may not be of any significance in natural immune responses.An example of this possibility can be found in studies performed in our laboratory in which we have shown that interferon-gamma was produced during infections of mice with the African trypanosome Trypanosoma brucei rhodesiense [1] . The interferon was produced only in those inbred strains of mice genetically resistant to infection with T. b. rhoclesiense, and production of interferon-gamma coincided with the production of antibody and the control of the first peak of parasitaemia by the mice [1]. Susceptible strains of mice produced little to no interferon when infected with the parasite, produced little to no antibody, and could not control the first peak of parasitaemia. The question can be asked, does the interferongamma produced by the resistant mice play a crucial role in regulating immune responses in the resistant mice, thus allowing them to control the parasitaemia? Alternatively, is the production of interferon-gamma just an indication that the resistant mice have a functional immune system that can respond to a mitogenic or antigenic stimulus from the trypanosome to produce interferon?There has been very little work done --in my opinion --to demonstrate that interferon plays a role in regulating normal immune responses. Two studies, both involving interferon-gamma, point to a significant natural role for interferon in regulating immune responses. They have involved different approaches, and both do strongly support an immunoregulatory function for interferon.In the first study, an antibody directed against murine interferongamma inhibited the development of an immune response. Farrar and his associates [2] have shown that interleukin-2 could regulate production of murine interferon-gamma and the generation of cytotoxic T lymphocytes (CTL) an a macrophage-depleted mixed lymphocyte culture. They prepared a polyelonal anti-murine interferon-gamma. This antibody neutralized the antiviral activity of inter-