The potential (therapeutic) role of BAFF, FLT3L and IL-2 in immune disorders

The TNF family member protein BAFF/BLyS is essential for B cell survival. In humans, increased \nconcentrations of soluble BAFF are found during different pathological conditions, which may be as \ndiverse as autoimmune diseases, B cell malignancies, and primary Ab deficiencies (PAD). We have \ndeveloped a sensitive ELISA for soluble human BAFF, which allows us to study some parameters that \nmight determine the level of soluble BAFF in circulation. We show that, patients suffering from PAD \nincluding severe functional B cell defects, such as BTK‐, BAFF‐R‐, or TACI‐deficiencies, were all found \nto have higher BAFF levels in their blood than asplenic individuals, patients having undergone anti‐ \nCD20 B cell depletion, chronic lymphocytic leukemia patients, or healthy blood donors. In a \ncomparable manner, transgenic mice constitutively expressing soluble human BAFF were found to \nhave higher concentrations of circulating human BAFF in the absence of B cells. Therefore, our data \nstrongly suggest that the steady‐state concentration of BAFF mainly depends on the number of B \ncells present as well as on the expression of BAFF‐binding receptors. Because most patients with PAD \nhave high levels of circulating BAFF, the increase in BAFF concentrations cannot compensate for the \ndefects in B cell development and function. \nIn a second study, we showed that treatment of mice with the fms‐like tyrosine kinase ligand (FLT3L) \nas well as with an IL‐2/αIL‐2 mAb complex (JES6‐1A12, S4B6) led to an expansion of the Treg \ncompartment. We show that this increased number of NTregs is due to proliferation of pre‐existing \nNTregs, likely due to favored interactions with the increased number of DCs. The increase of NTregs \nin the IL‐2/αIL‐2 complex treated mice is due to a direct effect of IL‐2 signaling. Thus the lifespan and \navailability of the IL‐2 molecules is prolonged due to the complex with the mAb and therefore \nstronger/longer signals via the IL‐2R can be achieved. We investigated the potential of FLT3L and IL‐ \n2/αIL‐2 pretreatment of mice and could show that administration of FLT3L could prevent death \ninduced by an acute GvHD in BDF1 mice. However, when we used a different mouse strain, \n(BM1xBM12)F1, no protection could be observed, even though the Treg cells increase in these mice \nwas similar to the one in BDF1 mice. By depleting the NK cell compartment of acute GvHD mice, we \ncould show that NTregs themselves are not protective in this system. \nIn a third study, the potential use of FLT3L and IL‐2/αIL‐2 complex (JES6‐1A12) pre‐treated recipients \nof solid allografts were investigated. To test whether Flt3L treatment was effective in prolonging \nallograft survival we used the transplant model where the tail skin from a BM12 mouse was \ntransferred to the trunk of B6 mice. An IL‐2/αIL‐2 complex pre‐treatment, previously shown to be \nhighly effective in a pancreatic islet allograft transplant model, was used as a control. All PBS treated \nB6 mice rejected the graft within 12 days, the IL‐2/αIL‐2 treated mice kept their allografts for a \nmaximum of 70 days +/‐ 5 days. In the FLT3L treated group, 12,5% of the mice rejected the graft with \nsimilar kinetics as the PBS treated mice. 62,5% of the mice showed a delayed rejection of the graft by \n4‐14 days. Only 25% of recipient mice had a graft survival similar to the IL‐2/αIL‐2 treated mice. \nReducing the numbers of Tregs in FLT3L treated mice by a αCD25 mAb injection resulted in a graft \nsurvival time similar to that observed in PBS treated mice suggesting that the FLT3L induced \nprolonged graft survival was due to increased numbers of Tregs. \nTaken together these findings indicate that FLT3L treatment could be a possible prophylactic therapy \nfor preventing solid organ rejection.