10th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals.

Therapeutic proteins and emerging gene and cell-based therapies are attractive therapeutic tools for addressing unmet medical needs or when earlier conventional treatment approaches failed. However, the development of an immune response directed against therapeutic agents is a significant concern as it occurs in a substantial number of cases across products and indications. The specific anti-drug antibodies that develop can lead to safety adverse events as well as inhibition of drug activity or accelerated clearance, both phenomena resulting in loss of treatment efficacy. The European Immunogenicity Platform (EIP) is a meeting place for experts and newcomers to the immunogenicity field, designed to stimulate discussion amongst scientists across industry and academia, encourage interactions with regulatory agencies and share knowledge and the state-of-the-art of immunogenicity sciences with the broader scientific community. Here we report on the main topics covered during the EIP 10th Open Symposium on Immunogenicity of Biopharmaceuticals held in Lisbon, 26-27 February 2019, and the 1-d training course on practical and regulatory aspects of immunogenicity held ahead of the conference. These main topics included immunogenicity testing, clinical relevance of immunogenicity, immunogenicity prediction, regulatory aspects, tolerance induction as a mean to mitigate immunogenicity and immunogenicity in the context of gene therapy.

Profound effect of the absence of IL-4 on T cell responses during infection with Schistosoma mansoni.

T cell responses of interleukin (IL)-4(-/-) and wild-type (WT) mice infected with the helper T cell 2 (Th2) response-inducing pathogen Schistosoma mansoni were compared. As expected, given the important role of IL-4 in Th2 response induction, the absence of IL-4 resulted in diminished Th2 responses, apparent as reduced production of IL-4, -5, and -10 by CD4(+) cells isolated from the spleens of infected IL-4(-/-) mice. Surprisingly, these cells produced significantly less interferon (IFN)-gamma and proliferated less than did those from infected WT mice after T cell receptor ligation. CD8(+) cells isolated from infected IL-4(-/-) mice also produced less IFN-gamma than WT CD8 cells, although there was no difference in the proliferative responses of these cell populations. After infection, spleens of infected IL-4(-/-) mice did not enlarge to the same extent as those of WT mice, and attrition of the CD8(+) cell population within this lymphoid organ was noted. Taken together, the data indicate that in addition to inhibiting Th2 response development, the lack of IL-4 during schistosomiasis significantly affects additional aspects of T cell responses.

Severe schistosomiasis in the absence of interleukin-4 (IL-4) is IL-12 independent.

An interleukin-4 (IL-4)-dependent Th2 response allows wild-type mice to survive infection with the parasite Schistosoma mansoni. In the absence of IL-4, infected mice mount a Th1-like proinflammatory response, develop severe disease, and succumb. Neither the Th1 response nor morbidity is IL-12 dependent in this system.

Schistosoma mansoni infection induces a type 1 CD8+ cell response.

We have found that infection with the large extracellular parasite S. mansoni leads to the development of a type 1 CD8+ T cell response. While there are many poorly understood aspects of this immune response, our working hypothesis is that it functions primarily to regulate the parasite egg-antigen induced Th2 response, which itself is responsible for circumoval granunuloma formation. This view of the activity of CD8+ cells mirrors Bloom and colleagues' postulate that type 2 CD8+ cells function to regulate Th1 responses. Since it is well recognized that Th1 and Th2 cells can cross regulate each other, why should a type 1 CD8+ rather than a Th1 response be used for the regulation of the Th2 response during schistosomiasis? The answer to this may in part lie in the apparent dependence of the type 1 CD8+ cells on IL-4. Because of this, there is little likelihood for the over-production of IFN-gamma (a potentially dangerous proinflammatory cytokine) and "suppression" is provided only when needed. Th1 cells have no such dependence on IL-4 for IFN-gamma production. Current work in the laboratory is directed towards testing the various hypotheses put forward here.

Type 1 CD8+ T cell responses during infection with the helminth Schistosoma mansoni.

IL-4 promotes the development of type 2 CD8+ T cells. In mice infected with the helminth Schistosoma mansoni, the Th response is overtly Th2-like, creating an environment rich in IL-4. Consequently, we examined whether CD8+ subset development in schistosome-infected mice is biased in a type 2 direction; this is of interest because CD8+ cells have been proposed to play an immunoregulatory role during schistosomiasis. Contrary to expectation, our data indicate that the CD8+ cell response in infected mice is strongly type 1-like. Thus, infection with S. mansoni leads to the development of concurrent Th2 and type 1 CD8+ cell responses. Cytokine production by type 1 CD8+ cells is dependent upon help from CD4+ cells; this helper activity can be substituted by exogenous IL-2 or IL-4. Since Th cells from infected mice make little IL-2 but large amounts of IL-4, we propose that IL-4 is likely to be the physiologic mediator of help in infected animals, a view supported by the ability of mAbs against IL-4R and IL-4 to reduce IFN-gamma production by splenocytes in vitro. CD8+ cells from infected mice are able to produce IFN-gamma in response to schistosome Ag presented by bone marrow-derived APC. A regulatory role for the CD8+ cells is implied by the observation that CD8+ cell-depleted splenocytes from infected mice exhibit increased proliferative responses and IL-4 production in response to mAb anti-CD3. These findings suggest that in mice infected with schistosomes there exists a regulatory pathway in which type 1 CD8+ cells, under the control of IL-4, dampen immunopathologic type 2 responses.