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      IFN-γ Mediates the Rejection of Haematopoietic Stem Cells in IFN-γR1-Deficient Hosts

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          Abstract

          Background

          Interferon-γ receptor 1 (IFN-γR1) deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation (HSCT) is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-γR1 deficiency.

          Methods and Findings

          We demonstrated that HSCT with cells from a syngenic C57BL/6 Ifngr1 +/+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL/6 Ifngr1 −/− recipients. However, Ifngr1 −/− mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rejected HSCT. Like infected IFN-γR1-deficient humans, infected Ifngr1 −/− mice displayed very high serum IFN-γ levels before HSCT. The administration of a recombinant IFN-γ-expressing AAV vector to Ifngr1 −/− naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1 −/− × Ifng −/− double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-γ depletion in infected Ifngr1 −/− mice in vivo allowed subsequent engraftment.

          Conclusions

          High serum IFN-γ concentration is both necessary and sufficient for graft rejection in IFN-γR1-deficient mice, inhibiting the development of heterologous, IFN-γR1-expressing, haematopoietic cell lineages. These results confirm that IFN-γ is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN- γR1-deficient patients through IFN-γ depletion from the blood. They further raise the possibility that depleting IFN-γ may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor.

          Abstract

          Claire Soudais and colleagues investigated the mechanism of rejection of hematopoietic stem cell transplants in patients with interferon-gamma receptor 1 (IFN-γR1) deficiency and show that IFN-γ is an anti-hematopoietic cytokine in vivo.

          Editors' Summary

          Background.

          Normally, the body's immune system efficiently recognizes and kills bacteria and viruses, but in some rare inherited disorders (“primary immunodeficiencies”) part of the immune system works poorly or is missing. This leaves affected individuals susceptible to infections. People with one of these disorders—interferon-gamma receptor 1 (IFN- γR1) deficiency—are very susceptible to infections with mycobacteria. Except for Mycobacterium tuberculosis and M. leprae (which cause tuberculosis and leprosy, respectively), mycobacteria rarely cause human disease. However, most people with IFN-γR1 deficiency die during childhood from multiple, widespread mycobacterial infections, because IFN-γR1 deficiency disables a specific part of their immune system. When most bacteria enter the body, immune system cells called macrophages engulf and kill them, but mycobacteria actually multiply inside macrophages. This infection stimulates lymphocytes and other immune system cells to release IFN-γ, which binds to IFN-γR1 on uninfected macrophages, activates them, and recruits them to the infection site. Here, they form a “granuloma,” a mass of macrophages and activated lymphocytes that “walls off” the infection. Granuloma formation does not occur in patients with IFN-γR1 deficiency, so mycobacteria (including the usually benign tuberculosis vaccination strain M. bovis BCG) spread throughout the body with disastrous consequences.

          Why Was This Study Done?

          The only effective treatment for patients with IFN-γR1 deficiency is hematopoietic stem cell transplantation (HSCT). HSCs are the source of all the immune system cells, so transplantation of HSCs from a donor with a normal IFNGR1 gene can provide a patient who has IFN-γR1 deficiency with a new immune system that can combat mycobacterial infections. Unfortunately, in this particular immune deficiency, the new HSCs cannot engraft, even when the patient's own immune system is disabled before HSCT by intensive chemotherapy, and when the donor cells come from a close relative and are a good immunological match. In this study, the researchers have investigated why rejection is so common in IFN-γR1 deficiency using a mouse strain called C57BL/6 Ifngr1 / C57BL/6 denotes the genetic background of these mice and Ifngr1 / indicates that, like human patients, these mice make no IFN-γR1.

          What Did the Researchers Do and Find?

          Ifngr1 / mice, the researchers report, cannot control M. bovis BCG infections and do not form mature granulomas just like human patients with IFN-γR1 deficiency. Wild-type C57BL/6 ( Ifngr1 +/+ ) mice, however, rapidly control M. bovis BCG infections and form mature granulomas. Ifngr1 +/+ HSC transplanted into mycobacteria-free Ifngr1 / mice survived well and protected the mice against later mycobacterial challenge but Ifngr1 / mice infected with M. bovis BCG before HSCT rejected the transplanted HSCs. Mycobacteria-infected Ifngr1 / mice and human patients with IFN-γR1 deficiency have blood high levels of IFN-γ. Could this be responsible for HSCT rejection? To find out, the researchers expressed IFN-γ in uninfected Ifngr1 / mice before HSCT. As in infected mice, these grafts failed. Conversely, transplanted HSCs survived when transplanted into Ifngr1 / mice that had been genetically altered to express no IFN-γ, even when these mice were infected with M. bovis BCG before transplantation. Finally, when the researchers used antibodies (proteins made by the immune system that recognize specific molecules) to remove circulating IFN-γ from infected Ifngr1 / mice, HSCT worked well in the animals with the lowest IFN-γ levels.

          What Do These Findings Mean?

          These findings indicate that in a mouse model of IFN-γR1 deficiency, high circulating IFN-γ concentrations drive the rejection of transplanted HSCs and prevent the development of antimycobacterial immunity, probably by directly killing the transplanted cells and/or stopping them multiplying. They also suggest how HSCT could be improved in patients with IFN-γR1 deficiency although, as with all animal studies, the situation in people might turn out to be very different. Importantly, antibodies that reduce circulating IFN-γ are already being used to treat other human immune diseases, so the clinical use of these antibodies in patients with IFN-γ deficiency before HSCT is feasible. Finally, the researchers speculate that the use of IFN-γ–depleting antibodies might be beneficial in other situations where HSCT often fails such as when a close relative is not available as a donor. However, this possibility will need to be thoroughly tested in mice before human clinical trials can be started.

          Additional Information.

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050026.

          Related collections

          Most cited references 57

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          Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders

          Online Mendelian Inheritance in Man (OMIM™) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic disorders compiled to support human genetics research and education and the practice of clinical genetics. Started by Dr Victor A. McKusick as the definitive reference Mendelian Inheritance in Man, OMIM (http://www.ncbi.nlm.nih.gov/omim/) is now distributed electronically by the National Center for Biotechnology Information, where it is integrated with the Entrez suite of databases. Derived from the biomedical literature, OMIM is written and edited at Johns Hopkins University with input from scientists and physicians around the world. Each OMIM entry has a full-text summary of a genetically determined phenotype and/or gene and has numerous links to other genetic databases such as DNA and protein sequence, PubMed references, general and locus-specific mutation databases, HUGO nomenclature, MapViewer, GeneTests, patient support groups and many others. OMIM is an easy and straightforward portal to the burgeoning information in human genetics.
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            An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection

            Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell- mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.
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              Genetic dissection of immunity to mycobacteria: the human model.

              Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                plme
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                January 2008
                29 January 2008
                : 5
                : 1
                Affiliations
                [1 ] Laboratoire de Génétique Humaine des Maladies Infectieuses, INSERM, U550, Paris, France
                [2 ] Université Paris René Descartes, Faculté de Médecine Necker-Enfants Malades, Paris, France
                [3 ] Hôpital Raymond Poincaré, Faculté de Médecine Paris-Ile de France-Ouest, UPRES Sud, EA3647, Laboratoire de Microbiologie, Garches, France
                [4 ] Institut Cochin, INSERM, U567, Paris, France
                [5 ] CNRS, UMR8104, Paris, France
                [6 ] Université René Descartes, Hôpital Cochin, Paris, France
                [7 ] Hôpital Ambroise Paré, Laboratoire d'Anatomo-Pathologie, Boulogne, France
                [8 ] Unité d'Immunologie et Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris, France
                Institute of Child Health, United Kingdom
                Author notes
                * To whom correspondence should be addressed. E-mail: soudais@ 123456necker.fr
                Article
                07-PLME-RA-0408R2 plme-05-01-23
                10.1371/journal.pmed.0050026
                2214797
                18232731
                Copyright: © 2008 Rottman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Genetics and Genomics
                Hematology
                Immunology
                Infectious Diseases
                Immunology and Allergy
                Pediatrics
                Tuberculosis
                Custom metadata
                Rottman M, Soudais C, Vogt G, Renia L, Emile JF, et al. (2008) IFN-γ mediates the rejection of haematopoietic stem cells in IFN-γR1-deficient hosts. PLoS Med 5(1): e26. doi: 10.1371/journal.pmed.0050026

                Medicine

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