[Pathological consequences of excess of interferon in vivo]. / Conséquences pathologiques d'un excès d'interféron in vivo - Comment ne pas sous-estimer des expériences in vivo quand elles peuvent paraître anecdotiques et non conformistes.

In this brief review, the authors present a history of the different aspects of the scientific puzzle leading from pioneer animal studies and astute clinical experimental observations to a mature appreciation of the deleterious role of excess of a type I interferon in human pathology.

Selective expression of inhibitory Fcgamma receptor by metastatic melanoma impairs tumor susceptibility to IgG-dependent cellular response.

During melanoma progression, patients develop anti-tumor immunity including the production of anti-tumor antibodies. Although the strategies developed by malignant cells to escape anti-tumor cellular immunity have been extensively investigated, little is known about tumor resistance to humoral immunity. The main effect of IgG antibodies is to activate the immune response by binding to host Fc gamma receptors (FcgammaR) expressed by immune cells. We previously reported in a limited study that some human metastatic melanoma cells ectopically express the FcgammaRIIB1, an inhibitory isoform of FcgammaR. By analyzing a large panel of different types of human primary and metastatic solid tumors, we report herein that expression of FcgammaRIIB is restricted to melanoma and is acquired during tumor progression. We show that FcgammaRIIB expression prevents the lysis of human metastatic melanoma cells by NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, independently of the intracytoplasmic region of FcgammaRIIB. Using experimental mouse models, we demonstrate that expression of FcgammaRIIB protects B16F0 melanoma tumors from the ADCC induced by monoclonal and polyclonal anti-tumor IgG in vivo. Thus, our results identify FcgammaRIIB as a marker of human metastatic melanoma that impairs the tumor susceptibility to FcgammaR-dependent innate effector responses.

Recombinant human IFN-alpha inhibits cerebral malaria and reduces parasite burden in mice.

Most C57BL/6 mice infected i.p. with Plasmodium berghei ANKA (PbA) die between 7 and 14 days with neurologic signs, and the remainder die later (>15 days) with severe anemia. Daily i.p. injections of a recombinant human IFN-alpha (active on mouse cells) prevented death by cerebral malaria (87% deaths in the control mice vs 6% in IFN-alpha-treated mice). The mechanisms of this IFN-alpha protective effect were multiple. IFN-alpha-treated, PbA-infected mice showed 1) a marked decrease in the number of PbA parasites in the blood mediated by IFN-gamma, 2) less sequestered parasites in cerebral vessels, 3) reduced up-regulation of ICAM-1 expression in brain endothelial cells, 4) milder rise of blood levels of TNF, 5) increased levels of IFN-gamma in the blood resulting from an increased production by splenic CD8+ T cells, and 6) fewer leukocytes (especially CD8+ T cells) sequestered in cerebral vessels. On the other hand, IFN-alpha treatment did not affect the marked anemia observed in PbA-infected mice. Survival time in IFN-alpha-treated mice was further increased by performing three blood transfusions over consecutive days.

The antitumor effects of interferon: a personal history.

Early experiments showed that administration of mouse interferon preparations inhibited the development of viral-induced or spontaneous viral associated leukemias in mice. Interferon alpha/beta was also shown to inhibit the growth of transplantable tumors of different origins in all strains of mice tested. The finding that interferon alpha/beta inhibited the growth of sublines of tumors selected for resistance to interferon alpha/beta indicated the role of interferon induced host mechanisms in the antitumor effects observed. The different host antitumor mechanisms and especially the interaction of interferon alpha/beta with the immune system have been briefly discussed. Injection of mice with a neutralizing antibody to interferon alpha/beta demonstrated the essential role of endogenous interferon alpha/beta in the defense of the mouse against the development of syngeneic, allogeneic and xenogeneic tumors.

Type I IFNs stimulate nitric oxide production and resistance to Trypanosoma cruzi infection.

The participation of type I IFNs (IFN-I) in NO production and resistance to Trypanosoma cruzi infection was investigated. Adherent cells obtained from the peritoneal cavity of mice infected by the i.p. route produced NO and IFN-I. Synthesis of NO by these cells was partially inhibited by treatment with anti-IFN-alphabeta or anti-TNF-alpha Abs. Compared with susceptible BALB/c mice, peritoneal cells from parasite-infected resistant C57BL/6 mice produced more NO (2-fold), IFN-I (10-fold), and TNF-alpha (3.5-fold). Later in the infection, IFN-I levels measured in spleen cell (SC) cultures from 8-day infected mice were greater in C57BL/6 than in infected BALB/c mice, and treatment of the cultures with anti-IFN-alphabeta Ab reduced NO production. IFN-gamma or IL-10 production by SCs was not different between the two mouse strains; IL-4 was not detectable. Treatment of C57BL/6 mice with IFN-I reduced parasitemia levels in the acute phase of infection. Mice deprived of the IFN-alphabetaR gene developed 3-fold higher parasitemia levels in the acute phase in comparison with control 129Sv mice. Production of NO by peritoneal macrophages and SCs was reduced in mice that lacked signaling by IFN-alphabeta, whereas parasitism of macrophages was heavier than in control wild-type mice. We conclude that IFN-I costimulate NO synthesis early in T. cruzi infection, which contributes to a better control of the parasitemia in resistant mice.

Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.

The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.

Type I interferons produced by dendritic cells promote their phenotypic and functional activation.

Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-alpha and IFN-beta, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti-IFN-alpha/beta antibody to purified splenic DCs in vitro partially blocked the "spontaneous" activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-gamma, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

Endogenous type I interferons as a defense against tumors.

We have reviewed the experimental results which indicate that endogenous type I interferon (IFN) present either constitutively or possibly induced by the tumor plays an important role in limiting the development of transplantable tumors in mice. Thus, treatment with potent polyclonal neutralizing antibodies to IFN alpha/beta markedly enhanced the subcutaneous growth, invasiveness and metastases of xenogeneic tumor cells (uninfected or infected with RNA or DNA viruses) in athymic nude mice; enhanced the intraperitoneal transplantability of six different syngeneic murine tumors in three strains of immunocompetent mice; and completely abrogated the resistance of allogeneic C57Bl/6 (H-2(b)) or C3H (H-2(k)) mice to the multiplication of Friend erythroleukemia cells (H-2(d)) in the liver and spleen resulting in the death of most mice. The mechanisms by which mice respond to the injection of relatively few tumor cells appear to be multiple, to depend on the site of tumor growth, to occur early and prior to an immunologic response. Endogenous type I IFN appears to constitute an essential component of these defense mechanisms enabling the host to restrict tumor growth.

Study on Cytotoxicity to Mouse 3CL-8 Cell of Friend Erythrocyte by 50% Dyers Woad (Isatis tinctoria) Injection in Vivo and in Vitro / 中草药

The paper presented here provides evidence of cytotoxicity to mouse 3CL-8 cell of friendcrythrocyte bY 50% Isatis tinctoria injection. In vitro this extract of traditional Chinese medicine exerts a strong cytostatic effect directly on mousc 3 CL-8 cell in tissue culture at a minimum concentration of 1 ∶80 dilution. In vivo, when injected subcutaneously aud locally ontumor site, it showed some cytotoxic effect on 3 CL-8, but showed no significant cytotoxiceffect intrapertoneally.