Expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, leukocyte function antigen-1 (LFA-1), after pancreatic islet transplantation may affect both nonspecific and alloantigen-specific phases of graft destruction. We examined the effects of ICAM-1/LFA-1 blockade on the survival of islet allografts. Fresh C57BL/10 (H2h) pancreatic islets were transplanted under the renal subcapsular space (KC) or embolized into the liver after portal vein (PV) injection to C3H (H2k) mice. Recipients remained untreated or were treated for 7 days by i.p. administration of: ICAM-1 antisense phosphorothioate oligodeoxynucleotide (oligo) alone; anti-1CAM-1 (alphaICAM-1) monoclonal antibody (mAb) alone: alphaLFA-1 mAb alone; ICAM-1 oligo/alphaLFA mAb combination; alphaICAM-1 mAb/alphaLFA-1 mAb combination; or control oligo IP-8997 or IP-1082. In some experiments, donors were pretreated with ICAM-1 oligo. Inhibition of single ligand with 5.0 mg/kg ICAM-1 oligo (25.1 +/- 10.3), 100 microg/daily alphaICAM-1 mAb (24.2 +/- 8.0 days), or 50 microg/daily alphaLFA-1 mAb (42.8 +/- 25.9 days) prolonged the survivals of KC islet allografts in comparison with untreated controls (11.9 +/- 1.0 days; all p < 0.01). However, dual ICAM-1/LFA-1 blockade with either ICAM-1 oligo/alphaLFA-1 mAb (78.3 +/- 16.5 days) or (alphaICAM-1 mAb/aLFA-1 mAb (65.2 +/- 31.3 days) was the most effective therapy. Although pretreatment of donors with ICAM-1 oligo alone was ineffective (12.2 +/- 0.8 days; NS), a combination of donor pretreatment and recipient treatment started 1 day prior to grafting with ICAM-1 oligo (39.2 +/- 14.0 days) was more effective than the recipient treatment alone (24.6 +/- 8.8 days). Furthermore, ICAM-1/LFA-1 blockade improved islet function as evaluated by glucose tolerance test, and decreased inflammation in comparison with untreated controls. Similar in vivo results were obtained following PV administration of islet allografts. Thus, ICAM-1/LFA-1 blockade prolongs the survival of pancreatic islet allografts and improves their early function.

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PubMedDate not supplied

Intrasplenic liver parenchymal cells in conjunction with low-dose rapamycin and cyclosporine induce a unique and specific prolongation of rat cardiac and small bowel allograft survival.

These experiments investigated the immunosuppressive properties of liver tissue. Brown Norway (BN; RT1n) rat heart allografts survived in untreated control Wistar Furth (WFu; RTl(u)) rat recipients for 6.2 +/- 1.5 days, while allografts in animals that received rapamycin (RAPA) 0.0075 mg/kg/day and cyclosporine (CsA) 0.375 mg/kg/day delivered for 14 days by continuous intravenous infusion (civi) using osmotic pumps in conjunction with intrasplenic (i.s.) saline survived to 18.4 +/- 1.3 days. i.s. addition of 3 M-KCl extracted BN hepatic antigen or unpurified BN hepatocytes (liver parenchymal cells-5 x 10(7)/kg), which exhibited a 4.8% class II antigen expression, and which alone failed to prolong allograft survival (MST = 6.0 +/- 1.4 days), increased heart allograft survival to 25.3 +/- 2.3 and 27.2 +/- 1.9 days, respectively (p < 0.01). Hepatocyte purification using Dynabeads and Percoll reduced class II expression to 0.9% and increased allograft survival to 32.8 +/- 1.6 days (p < 0.01). In contrast, the effect of 5 x 10(8)/kg BN erythrocytes, exhibiting only 0.1% class II expression, was much less (23.8 +/- 1.9 days). Administration i.s. of BN splenocytes or nonparenchymal liver cells, demonstrated by flow cytometry to exhibit a 47.3 or 55.1% expression of class II antigen, respectively, failed to induce any significant increase in allograft survival (18.4 +/- 4.6 and 19.4 +/- 0.5 days, respectively). Survival of BN rat small bowel allografts was increased in Lewis (LEW; RTl1) rat recipients treated with RAPA, CsA, and unfractionated BN hepatocytes from 10.2 +/- 1.9 to 21.2 +/- 1.5 days. Pretreatment with i.s. BN hepatocytes, 14 days prior to harvesting, reduced WFu lymphocyte responses to allogeneic stimulation with BN or ACI spleen cells by 75 and 70%, respectively. Addition of 1 x 10(5) unpurified donor-specific BN or third-party Buffalo (BUF; RTl(b)) hepatocytes, but not supernatant, to the responder wells of MLCs resulted in a 61 and 40% suppression, respectively, of the WFu lymphocyte response induced by BN allogeneic stimulation. These findings suggest that while class I MHC expression has a significant role to play in exerting the immunosuppressive effects of hepatocytes, other influences more specific to liver may also prevail.

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