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Fludarabine phosphate selectively eliminates normal and malignant mononuclear cells in large animals and man through the inhibition of DNA synthesis. The drug depletes mononuclear cells from culture within 24 hours of initial exposure, CD4 and CD8 T cells being more sensitive than either CD20 B cells or CD34 bone marrow precursors. Mitogenic activation of lymphocytes enhances cellular elimination from culture. Fludarabine inhibits PHA-induced T-cell proliferation by90 per cent and mixed lymphocyte reactions (allogeneic and xenogeneic) by95 per cent. Fludarabine exerts its cytolytic effects through the induction of endonuclease-independent apoptosis. A 5-day course of fludarabine (50 mg/m2 intravenously once daily) induces both T- and B-cell lymphopenia in Cynomolgus monkeys and Papio baboons. Transient neutropenia was the only side-effect seen in experimental animals. Pretreatment of Cynomolgus monkeys with this regimen of fludarabine causes a prolongation of ABO-compatible skin allograft survival from 8 days (control) to 16 days (drug treated group). Secondary allotransplantation into presensitized recipients showed a similar prolongation of graft survival with fludarabine pretreatment (8 days vs 5 days control). Fludarabine promises to be a potent immunosuppressive agent with low clinical toxicity.

The recovery of pancreatic islet cells from cadaveric donors for allotransplantation may depend on the functional condition of the pancreas of the donor prior to organ harvesting. We examined donor hemodynamic and biochemical parameters and their effects on the subsequent yield of islet cells after harvesting. All pancreata were flushed and preserved in University of Wisconsin (UW) solution and digested using automated method within 8 hours. In the first analysis, digestions were divided into high-yield (2000 IEQ/g pancreas), and low-yield (2000 IEQ/g) groups and donor variables were averaged for each group. Donors whose pancreata yielded2000 IEQ/g received significantly greater amounts of Dopamine (14.43 micrograms/kg/min vs 9.35 mg/kg/min, p = 0.05). The daily urine output between groups was also significantly different. Maximum systolic blood pressure (SBP), minimum systolic blood pressure, use of vasopressin, length of hospitalization, and maximum base deficit were compared between the two groups. Less severe hypoglycemia (lowest blood glucose 143 mg/dL vs 107 mg/dL, p = 0.02) and lower amylase levels (36.2 U vs 80.7, p = 0.07 were noted in the high-yield group. A trend towards higher islet yields was associated with lowest hourly urine output60 (2040 IEQ/g vs 1649 IEQ/g p = 0.09), maximum SBP200 (2097 vs 1673, p = 0.07, and surprisingly, lowest SBP below 80 (2013 vs 1742, p0.1). Amount of fluids administered prior to procurement had no influence on islet yield. In conclusion, hemodynamic variables such as urine output, systolic blood pressure, and degree of pressor support were modestly associated with successful islet isolation. The preliminary data suggest that better multifactor donor analysis is imperative for standardization and monitoring of multiorgan donors. The association of higher blood glucose levels with successful isolation may also be related to resuscitation with dextrose-containing fluids.