Polti Franco

Inhibitory effect of somatostatin on human T lymphocytes proliferation

Somatostatin (SOM) was originally described as a growth hormone release inhibiting factor, but SOM and its specific receptors (SOM-r) have been shown to be expressed on both normal and activated T and B lymphocytes and other immunocompetent cells. In the present study we have demonstrated that SOM strongly inhibits the proliferation of human T lymphocytes when stimulated by PHA, Con A or alloantigens. However, SOM was most effective when the T cells were stimulated by an alloantigen rather than a polyclonal activator such as PHA and ConA. Moreover, SOM strongly inhibited the expression of activation markers such as CD69 and CD25 that are expressed on T lymphocytes during alloantigen stimulation. SOM also inhibited both CD28 and CD2 mediated T cell proliferation. Whereas proliferation of T cells induced by the engagement of CD3 antigen using specific mAbs was only marginally affected. Our results would support the concept that in humans SOM plays a key role in the modulation of T cell activation by interfering with the antigen-independent pathways CD2 and CD28.

Inhibitory effect of pasireotide and octreotide on lymphocyte activation

Somatostatin (SST) regulates the function of the central and peripheral nervous system, the endocrine and exocrine organs, as well as the vascular and immune system. These actions are mediated by five specific membrane somatostatin receptors. This study compares the effects on human lymphocytes of two long-acting somatostatin analogues that have different receptor affinity: octreotide and pasireotide. Both analogues have an antiproliferative effect on human lymphocyte proliferation, but they act at different concentration and, while octreotide enhances IL10 and inhibits gamma IFN pasireotide inhibits IL2 and gamma IFN. In both sets of experiment the different behaviour of the two analogues could be due to their different affinity to the SSTR subtypes. Finally this study suggest that the growth inhibitory action of somatostatin analogues is an apoptotic phenomenon and it can be mediated by SSTR2a, in the case of octreotide, and by SSTR3 when pasireotide is used or it can be mediated by the heterodimerization of the two receptor.

Evidence that SMS 201-995 enhances the immunosuppressive effect of FK506

Somatostatin (SS) was originally described as a growth hormone release inhibiting factor synthesised in the hypothalamus. Recently, SS and its receptor (SSTR) have been demonstrated in lymphoid tissues and seem to play a regulatory, largely inhibitory, role in immune responses. The aim of the present study was to check the immunosuppressive effect of a SS derived peptide, the octreotide (SMS 201-995) and to verify whether this molecule acted synergistically with FK506. An immunosuppressive effect of SMS was observed on the proliferation of rat spleen cells induced in vitro, either by polyclonal mitogens such as PHA or by alloantigens. With PHA stimulation, 10(-14) M SMS significantly enhanced the immunosuppressive action of 0.00001 microg/ml FK506. The addition of SMS in MLR (10(-11)-10(-9)M) increased the antiproliferative effect of both 0.0001 microg/ml and 0.00001 microg/ml FK506. In consideration of the extremely low concentration of both drugs that was required to obtain a good immunosuppression in vitro, we verified the association of FK506 and SMS in vivo in an allogeneic skin graft model that used Lewis (Lew) rats as donors and Brown Norway (BN) rats as recipients. BN treated with 0.1 mg/kg FK506 and 0.5-10 microg/kg SMS showed a significant increase in mean skin allograft survival time when compared to either a monotherapy or control group. None of the animals died or showed signs of drug-related toxicity. In conclusion, a combined therapy of SMS and FK506, administered at lower dosages than those that are considered therapeutic, led to an effective immunosuppression without any undesirable side effects.

Effects of chimeric somatostatin–dopamine molecules on human peripheral blood lymphocytes activation

BIM 23A761, selective for somatostatin receptors subtypes 2, 5 and the dopamine receptor subtype 2, and BIM 23A757 with affinity for SSTR2 and DAR2 were studied on human PBL proliferation and activation. BIM 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen, while BIM 23A757 was more potent than specific SSTR2 and DAR2 agonists in suppressing antigen induced proliferation only. Both molecules displayed enhanced potency in suppressing IFNgamma and IL-6 secretion compared with the SSTR and DAR2 analogs, while only BIM 23A761 was able to inhibit IL-2 secretion and its effect is more potent than the control analogs. Furthermore BIM 23A761 inhibit cell progression into the S phase and then into the G2/M, while BIM 23A757 inhibited bromodeoxyuridine incorporation only during the S phase. Both chimeric molecules resulted significantly more effective than the respective controls.

Transplantation of small bowel alone or with the liver in pigs : Use of peripheral blood lymphocytes in monitoring rejection

Abstract The small bowel is an organ with a large lymphoid component. In addition to the organized structures of the Peyers patches and mesenteric lymph nodes, the lamina propria also contains a vast mass of mobile lymphocytes. The transplantation of the small bowel has thus been associated with significant rejection phenomena and the possibility of graft-versus-host disease (GVHD) in the recipient, despite the immunosuppressive treatment. In a swine model, we have compared by mixed lymphocyte reaction (MLR) the immunological events occurring during orthotopic liver-small bowel transplantation (OLSBTx) and small bowel transplantation alone (SBTx) to evaluate a possible immunological advantage of combined liver-small bowel transplantation in order to prevent intestinal rejection.