Functional topography of discrete domains of human CD38

In addition to its catalytic activities as ecto-NAD(+) glycohydrolase (NADa se), CD38 displays the ability to transduce signals of biological relevance . Indeed, ligation of CD38 on peripheral blood mononuclear cells (PBMC) by agonistic monoclonal antibodies (mAbs) is followed by the transcription and secretion of a vast array of regulatory cytokines. The present work addres ses the issue of whether the signals leading to calcium (Ca2+) mobilization , lymphocyte proliferation and release of cytokines is dependent on the epi topes recognized by the individual mAbs. Competition binding analysis ident ifies two families of mAbs, namely IB4, IB6 and AT2 on one side and OKT10, SUN-4B7 and AT1 on the other. Each mAb family binds epitopes that are compl etely or partially common. However. the functional activities of the CD38 m olecule can not be simply attributed to the epitopes engaged: for instance, IB4 and OKT10 mAbs, which bind different epitopes, perform as agonistic mA bs in inducing PBMC proliferation and interferon (IFN)-gamma secretion. SUN -4B7 yields intermediate effects, whereas IB6, ATI and AT2 mAbs are totally ineffective. The effects mediated by IB4 and OKT10 mAbs are apparent in 80 % of the healthy individuals studied, whereas the effects of SUN-4B7 mAb op erate only in 25% of the donors. Interleukin (IL)-6 secretion was observed in all individuals analyzed, irrespective of the epitopes triggered and of mAbs used to ligate the CD38 molecule. In addition, IB4 is the only mAb abl e to induce significant intracellular Ca2+ fluxes.