Study and manipulation of

tolerance in human immunopathology

Team Leader :

Gorochov Guy

Contact the team

Our team has a longstanding interest in the study of immune responses against viruses, in particular those associated with autoimmunity or immune deficiency disorders, as well as, more recently, SARS-CoV-2. We expect that the development of biologics targeting auto-antigens, acting as competitive blockers, or used as mediators of specific T cell-mediated tolerance, will pave the way for the development of novel personalized therapies.

We are currently working on the generation of human patient-derived therapeutic monoclonal antibodies with the aim to develop i) biologics that specifically interfere with the activity of deleterious auto-antibodies, ii) regulatory T cells, expressing chimeric antigen receptors to treat various clinical disorders and iii) novel ways to restore immune/microbiota homeostasis in settings of dysbiosis.

Keywords : IgA – Treg – Microbiota – Antibody engineering – Autoimmunity – Anti-viral immunity

Combating COVID-19. These computerized tomography scans of the chest from patients with COVID-19 reveal ground glass opacities (blue) and lung consolidations (gray) dispersed throughout healthy tissue (yellow). Sterlin et al. characterized early antibody responses in the serum, saliva, and bronchoalveolar lavage fluid of 159 patients with COVID-19. The authors found that immunoglobulin (Ig)A antibodies dominated the early immune response, whereas IgG antibodies were more common at later time points after symptom onset. Further, IgA antibodies isolated from the saliva and bronchioalveolar lavage fluid efficiently neutralized severe acute respiratory syndrome coronavirus 2. These findings suggest that vaccines which induce SARS-CoV-2–specific IgA antibody responses could provide protection in the lungs and respiratory tract. [CREDIT: P. QUENTRIC, A. MATHIAN, AND G. GOROCHOV/AP-HP SORBONNE UNIVERSITÉ]
Commensal Curation by IgA. Pictured here is one of billions of bacteria in the gut that can be recognized and bound by mucosal IgA. Mouse models of IgA deficiency exhibit profound microbial-dependent defects that are not observed in humans naturally deficient in IgA. To discern the role of IgA in human gut health, Fadlallah et al. examined the fecal microbiome from healthy people and IgA-deficient patients. Although IgM could partially compensate for the lack of IgA to prevent overt microbial imbalance, different bacteria were prominent in the two groups of people. Their findings show how IgA curates gut bacteria to shape the microbiome in humans. [CREDIT: FADLALLAH ET AL./SCIENCE TRANSLATIONAL MEDICINE]

The team members

GOROCHOV Guy

GOROCHOV Guy

Team Leader

AMOURA Zahir

AMOURA Zahir

PU-PH / SU AP-HP

ATTIF Muhammad

ATTIF Muhammad

Doctorant / Inserm

BEN SALAH Elyes

BEN SALAH Elyes

Post-Doc / Inserm

CHASSET François

CHASSET François

MCU-PH / SU-APHP

CHERAI Mustapha

CHERAI Mustapha

IR / AP-HP

COHEN-AUBART Fleur

COHEN-AUBART Fleur

PU-PH / SU-APHP

DORGHAM Karim

DORGHAM Karim

IR1/Inserm

HAROCHE Julien

HAROCHE Julien

PU-PH / AP-HP

HUNAULT Lise

HUNAULT Lise

Doctorante

IMAMOVIC Lejla

IMAMOVIC Lejla

IR

FADLALLAH  Jehane

FADLALLAH Jehane

AHU / AP-HP

MATHIAN Alexis

MATHIAN Alexis

PH / AP-HP

MIYARA Makoto

MIYARA Makoto

MCU-PH / AP-HP

MORENO-SABATER Alicia

MORENO-SABATER Alicia

MCU-PH / SU-APHP

NGUYEN Ngoc-Khanh

NGUYEN Ngoc-Khanh

Post-Doc/AP-HP

PARIZOT Christophe

PARIZOT Christophe

IR / AP-HP

PINETON DE CHAMBRUN Marc

PINETON DE CHAMBRUN Marc

PhD/AP-HP

STERLIN Delphine

STERLIN Delphine

MCU-PH

UZUNNAN Yurdagul

UZUNNAN Yurdagul

PU-PH / SU-APHP

YSSEL Hans

YSSEL Hans

DR Emerite/Inserm

Our research focus on 3 axes

1. Host/microbiota mutualism in antibody deficiencies and dysbiotic states

It is now well-established that an imbalance between the interactions of the host and
its microbiota in a state of dysbiosis of the digestive tract may significantly affect
host immunity, as we have recently observed in multiple sclerosis patients. Moreover, this imbalance is believed to cause systemic complications associated with antibody deficiency, such as variable common immune deficiency (CIVD) or IgA deficiency. Our research program aims to provide proof of concept of the usefulness of antibody supplementation strategies to regulate dysbiosis. A large part of this program is dedicated to evaluating the potential of recombinant human IgA antibody cocktails to interact with broadly shared bacterial motifs and prevent or regulate dysbiosis in an experimental mouse model of IgA deficiency.
In addition, with respect to the host/microbiota interface, our laboratory is actively engaged in the generation and characterization of antibodies specific for pathobionts in order to propose novel approaches for the prevention or treatment of C. difficile infections.

2. Therapeutic human antibodies

There is clear evidence for the notion that the pathogenesis of certain diseases is directly related to the activity of auto-antibodies. Our laboratory has developed a project with the aim to isolate these pathogenic antibodies, derived from B cells of patients with different forms of autoimmunity, and to create therapeutic blocking antibodies that are capable to functionally compete with the corresponding pathogenic antibodies.
These antibodies would be useful either in a soluble form or in the form of chimeric T
receptors (CAR, see below). The concept of the “reversal” of pathological autoantibodies for use in biotherapy could be applied to a wide variety of pathologies, such as neuromyelitis optica, COVID-19 or autoimmunity associated with primary antibody deficiency.

These autoantibodies could also represent an interesting biotechnological resource. For example, the availability of neutralizing antibodies directed against type I interferons, whose presence we reported to be present in a population of patients with particularly severe forms of COVID-19, would be useful to extend possibilities of cytokine detection by digital Elisa technology (SIMOA) or treatment of Lupus patients characterized by an increase in the expression of genes regulated by type I interferons (“interferon signature”).

3. Immune cell therapy in transplantation, autoimmunity, tissue repair and cancer

Treg cell therapy has promising therapeutic potential for the treatment of autoimmune
diseases or for the induction of operational tolerance in solid organ transplantation. A problematic aspect of human Treg cells however is their instability in terms of phenotype, specific epigenetics and suppressive function both in vitro and in vivo. By combining proteomics and transcriptomics at the single cell level we aim to identify, targetable, factors that are responsible for this instability and via the modulation of their function aim to develop a fully optimized GMP expansion protocol for therapeutic Treg cells.
Using the latest technological advances in analysis, called MultiOmics, we study these cells at the unicellular level in IPEX disease and in ongoing phase I trials of Treg cell therapy in kidney and liver transplantation. Given the observation that Treg cells also play an important role in tissue repair, especially in inflammatory conditions, we therefore plan to manipulate tissue Treg cell in order to propose new therapeutic strategies for regenerative medicine.
CD15s, also known as sialyl Lewis x molecule, enables the transmigration of leukocytes into tissues through its interaction with E-selectin (CD62-E) expressed by endothelial cells. A process called exofucosylation increases CD15s expression, thereby enhancing CAR-T cell anti-tumor activity by facilitating their migration into tumors. We aim at evaluating this effect on CAR-T cells in various preclinical experimental tumor models.
Our laboratory is furthermore interested in the generation of therapeutic Treg cells expressing chimeric antigen receptors (CAR-Treg) for treatment of solid cancers.

The opportunities

  • Polyclonal Treg cell therapy clinical trials in transplantation and autoimmunity
  • Oral IgA supplementation of IgA deficiency
  • Microbiota-based biomarkers of disease progression in auto-immunity and
    immunodeficiencies
  • Human, patient-derived, therapeutic monoclonal antibodies

Publications

1.

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. Manry J, Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Michailidis E, Hoffmann HH, Eto S, Garcia-Prat M, Bizien L, Parra-Martínez A, Yang R, Haljasmägi L, Migaud M, Särekannu K, Maslovskaja J, de Prost N, Tandjaoui-Lambiotte Y, Luyt CE, Amador-Borrero B, Gaudet A, Poissy J, Morel P, Richard P, Cognasse F, Troya J, Trouillet-Assant S, Belot A, Saker K, Garçon P, Rivière JG, Lagier JC, Gentile S, Rosen LB, Shaw E, Morio T, Tanaka J, Dalmau D, Tharaux PL, Sene D, Stepanian A, Mégarbane B, Triantafyllia V, Fekkar A, Heath JR, Franco JL, Anaya JM, Solé-Violán J, Imberti L, Biondi A, Bonfanti P, Castagnoli R, Delmonte OM, Zhang Y, Snow AL, Holland SM, Biggs CM, Moncada-Vélez M, Arias AA, Lorenzo L, Boucherit S, Anglicheau D, Planas AM, Haerynck F, Duvlis S, Ozcelik T, Keles S, Bousfiha AA, El Bakkouri J, Ramirez-Santana C, Paul S, Pan-Hammarström Q, Hammarström L, Dupont A, Kurolap A, Metz CN, Aiuti A, Casari G, Lampasona V, Ciceri F, Barreiros LA, Dominguez-Garrido E, Vidigal M, Zatz M, van de Beek D, Sahanic S, Tancevski I, Stepanovskyy Y, Boyarchuk O, Nukui Y, Tsumura M, Vidaur L, Tangye SG, Burrel S, Duffy D, Quintana-Murci L, Klocperk A, Kann NY, Shcherbina A, Lau YL, Leung D, Coulongeat M, Marlet J, Koning R, Reyes LF, Chauvineau-Grenier A, Venet F, Monneret G, Nussenzweig MC, Arrestier R, Boudhabhay I, Baris-Feldman H, Hagin D, Wauters J, Meyts I, Dyer AH, Kennelly SP, Bourke NM, Halwani R, Sharif-Askari FS, Dorgham K, Sallette J, Sedkaoui SM, AlKhater S, Rigo-Bonnin R, Morandeira F, Roussel L, Vinh DC, Erikstrup C, Condino-Neto A, Prando C, Bondarenko A, Spaan AN, Gilardin L, Fellay J, Lyonnet S, Bilguvar K, Lifton RP, Mane S; HGID Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James’s Hospital, SARS CoV2 Interest Group; French COVID Cohort Study Group; Imagine COVID-Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank Investigators; COVID Human Genetic Effort; CP-COVID-19 Group; CONSTANCES cohort; 3C-Dijon Study; Cerba Health-Care; Etablissement Français du Sang Study group, Anderson MS, Boisson B, Béziat V, Zhang SY, Andreakos E, Hermine O, Pujol A, Peterson P, Mogensen TH, Rowen L, Mond J, Debette S, de Lamballerie X, Burdet C, Bouadma L, Zins M, Soler-Palacin P, Colobran R, Gorochov G, Solanich X, Susen S, Martinez-Picado J, Raoult D, Vasse M, Gregersen PK, Piemonti L, Rodríguez-Gallego C, Notarangelo LD, Su HC, Kisand K, Okada S, Puel A, Jouanguy E, Rice CM, Tiberghien P, Zhang Q, Casanova JL, Abel L, Cobat A. Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2200413119. doi: 10.1073/pnas.2200413119. Epub 2022 May 16. PMID: 35576468 Free article.

2.

Moyon, Sterlin D, Miyara M, Anna F, Mathian A, Lhote R, Ghillani-Dalbin P, Breillat P, Mudumba S, de Alba S, Cohen-Aubart F, Haroche J, Pha M, Du Boutin TD, Chaieb H, Flores PM, Charneau P, Gorochov G, Amoura Z. BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus. Ann Rheum Dis. 2021

3.

Sterlin D, Mathian A, Miyara M, Mohr A, Anna F, Clear L, Quentric P, Fadlallah J, Ghillani P, Gunn C, Hockett R, Mudumba S, Guihot A, Luyt C.E, Mayaux J, Beurton A, Fourati S, Lacorte J.M, Yssel H, Parizot C, Dorgham K, Charneau P, Amoura Z, Gorochov G.
IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med 2021

4.

Sterlin D, Larsen M, Fadlallah J, Parizot C, Vignes M, Autaa G, Dorgham K, Juste C, Lepage P, Aboab J, Vicart S, Maillart E, Gout O, Lubetzki C, Deschamps R, Papeix C, Gorochov G Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm 2021

5.

Emile JF, Cohen-Aubart F, Collin M, Fraitag S, Idbaih A, Abdel-Wahab O, Rollins BJ, Donadieu J, Haroche. Histiocytosis. Review. Lancet 2021

6.

Dorgham K, Quentric P, Gökkaya M, Marot S, Parizot C, Sauce D, Guihot A, Luyt C-E, Schmidt M, Mayaux J, Beurton A, Le Guennec L, Demeret S, Ben Salah E, Mathian A, Yssel H, Combadiere B, Combadiere C, Traidl-Hoffmann C, Burrel S, Pharm D, Marcelin A.G, Amoura Z, Voiriot G, Neumann AU, Gorochov G.
Distinct cytokine profiles associated with COVID-19 severity and mortality. J Allergy Clin Immunol 2021

7.

Sterlin D, Fadlallah J, Adams O, Fieschi C, Parizot C, Dorgham K, Rajkumar A, Autaa G, El-Kafsi H, Charuel J-L, Juste C, Jönsson F, Candela T, Wardemann H, Aubry A, Capito C, Brisson H, Tresallet C, Cummings RD, Larsen M, Yssel H, von Gunten S, Gorochov G. Human IgA binds a diverse array of commensal bacteria. J Exp Med 2020

8.

Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D’Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort, Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM¶, Gorochov G¶, Jouanguy E¶, Rice CM¶, Cobat A¶, Notarangelo LD¶, Abel L¶, Su HC#, Casanova JL#. #, ¶ : Equal contributions. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020

9.

Fadlallah J, Sterlin D, Fieschi C, Parizot C, Dorgham K, El Kafsi H, Autaa G, Ghillani-Dalbin P, Juste C, Lepage P, Malphettes M, Galicier L, Boutboul D, Clément K, André S, Marquet F, Tresallet C, Mathian A, Miyara M, Oksenhendler E, Amoura Z, Yssel H, Larsen M, Gorochov G. Synergistic convergence of microbiota-specific systemic IgG and secretory IgA. J Allergy Clin Immunol 2019

10.

Mathian A, Mouries-Martin S, Dorgham K, Devilliers H, Yssel H, Garrido Castillo L, Cohen-Aubart F, Haroche J, Hié M, Pineton de Chambrun M, Miyara M, Pha M, Rozenberg F, Gorochov G, Amoura Z. Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse.
Ann Rheum Dis 2019

11.

Fadlallah J, El Kafsi H, Sterlin D, Juste C, Parizot C, Dorgham K, Autaa G, Gouas D, Almeida M, Lepage P, Pons N, Le Chatelier E, Levenez F, Kennedy S, Galleron N, Pais de Barros JP, Malphettes M, Galicier L, Boutboul D, Mathian A, Miyara M, Oksenhendler E, Amoura Z, Doré J, Fieschi C, Dusko Ehrlich SSD, Larsen M, Gorochov G. Microbial ecology perturbation in human IgA deficiency. Sci Transl Med 2018

12.

Miyara M, Chader D, Sage E, Sugiyama D, Nishikawa H, Bouvry D, Claër L, Hingorani R, Balderas R, Rohrer J, Warner N, Chapelier A, Valeyre D, Musset L, Kannagi R, Sakaguchi S, Amoura Z, Gorochov G. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans.
Proc Natl Acad Sci USA 2015