Alternative pathways for the development of lymphoid structures in humans.

Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.

Immunotherapy of inflammatory diseases, 2005.

The management of inflammatory diseases has entered a new era, marked by the rise of new immunotherapy strategies. This concept was born thanks to the increasingly precise comprehension of their mechanism and the development of new therapeutic biological tools; progress that is probably as important as the discovery of steroids half a century ago. The use of biotherapies is now widespread, and, to date, approximately 1 million patients in the world have been treated with anti-TNF. Large-scale immunotherapy has requirements of which one should be aware. It is essential that users acquire a very high level of qualification. For handling biotherapies well, it is necessary to know the characteristics of biological tools (monoclonal antibodies, soluble receptors); in particular, their mode of action and their pharmacokinetic and pharmacodynamic properties. To optimise the use of these molecules, it is essential to know not only their characteristics but also the individual factors which make it possible to predict effectiveness and tolerance. Various approaches will allow a true 'pharmacoprediction' in order to determine 'the right drug for the right patient'. Thus, if this objective is achieved, it might be possible, in the immediate future, to propose à la carte therapeutic strategies, which avoid the most severe effects associated with the successive use of empirical immunosuppressor treatments. Lastly, it is essential for experts to identify new therapeutic strategies. This can be done only by mastering the most relevant advances of immunopathology, beyond the experimental models which are often difficult to extrapolate in humans. Thanks to this, original strategies, such as the modulation of costimulation pathways or the inhibition of mast cells, can be explored. This supplement is the synthesis of a conference on immunotherapies which gathered biologists and doctors of different horizons, all experts in biotherapies. The objective of this meeting can be summarised in two keywords: to understand and anticipate. These two concepts are essential for a specialist in immunomodulatory therapeutics. Thus, we hope that the information, brought by acknowledged experts, will enable you to enhance your knowledge on immunotherapies for the benefit of patients. Thank you for having allowed us to discover with enthusiasm these original aspects of modern immunotherapies of inflammatory diseases. See you soon at the 2006 conference.