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PubMed1993

New immunosuppressive agents.

In summary, many new modalities of immunosuppression after transplantation are being investigated (Fig. 1). These approaches include various new drugs or monoclonal antibodies that target different cell subsets, cellular activation pathways, cellular effector function or mediators (such as cytokines) of effector function, ligands that stabilize cellular interactions, or antimetabolites that preferentially affect lymphocytes (Tables 4 and 5). Because of the excellent early graft and patient survival results after liver transplantation under various current immunosuppressive protocols, future clinical trials using these various new modalities will require large numbers of patients to show statistically significant differences in graft or patient survival. Therefore, other criteria in addition to graft and patient survival must be analyzed to evaluate the importance of new immunosuppressive therapies. These criteria may include incidence of acute or chronic rejection, long-term graft function, incidence of infectious complications, length of hospitalization, drug toxicity, and patient tolerance and compliance with new therapies.

Alprostadil↗
PubMed1995

The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice.

The effects of cyclosporine (CsA), sirolimus (RAPA), and/or brequinar (BQR) were examined in a vascularized heterotopic heart transplant model in mice. Untreated C3H (H-2k) recipients reject C57 BL/10 (H-2b) heart allografts at a mean survival time (MST) of 7.7 +/- 1.4 days. A 7-d intravenous (i.v.) infusion by osmotic pump of CsA at doses of 5.0, 10.0, or 20.0 mg/kg extended heart allograft survival to 9.8 +/- 1.3 d (NS), 15.0 +/- 5.1 d (P < 0.01) or 15.0 +/- 1.9 d (P < 0.01), respectively. RAPA delivered i.v. for 7 d at a dose of 0.1 mg/kg produced an MST of 13.0 +/- 7.5 d; 0.2 mg/kg, 20.0 +/- 10.9 d; and 0.4 mg/kg, 15.8 +/- 4.1 d (all P < 0.01). A 7-d alternate-day (q.o.d.) course of oral gavage with BQR (0.5, 1.0, or 2.0 mg/kg) produced survivals of 12.0 +/- 2.4 d, 17.6 +/- 3.4 d, and 20.0 +/- 4.1 d, respectively (all P < 0.01). The combination of 2.5 mg/kg CsA with 0.05 mg/kg RAPA extended graft survival to 18.2 +/- 2.9 d (P < 0.01), and 5.0 mg/kg CsA with 0.1 mg/kg RAPA prolonged survival to 23.0 +/- 9.0 d (P < 0.01). These combinations represent synergistic interactions based upon combination index (CI) values of 0.1-0.6. Although 7-d courses of 0.5 mg/kg CsA (7.3 +/- 1.0 d; NS), 0.01 mg/kg RAPA (7.6 +/- 0.9 d; NS), or 0.125 mg/kg BQR (7.6 +/- 0.9 d; NS) were individually ineffective, the triple-drug combination prolonged the MST to 64.6 +/- 32.7 d (P < 0.005; CI = 0.001), with 2/5 grafts beating for more than 100 d. Similar results were produced by 14-day therapy in the BALB/c (H-2d) to C3H combination.

Animals↗
PubMedDate not supplied

Combination therapy with Brequinar sodium and cyclosporine synergistically prolongs hamster-to-rat cardia xenograft survival.

The accelerated rejection of hamster cardiac xenografts by Lewis rat recipients is due primarily to a humoral immune response. Traditional immunosuppressive agents, including cyclosporine, FK 506, and rapamycin, have not been effective in prolonging the rejection of xenografts in this model. We have recently examined the ability of the combination of cyclosporine and a new immunosuppressive agent, Brequinar sodium, to prevent the rejection of hamster xenografts. Prolongation of xenograft survival by treatment with Brequinar sodium alone (3 mg/kg/day) was minimally effective, with a median survival of 5.5 days. Conversely, a combination of Brequinar sodium (3 mg/kg/day) and cyclosporine (10 mg/kg/day), was associated with a significant prolongation of median graft survival (> 100 days). A quantitative analysis of the dose-effect relationship of Brequinar sodium and cyclosporine demonstrated a potent synergistic interaction for this combination therapy (combination index < 1). A sharp increase occurred in the binding of immunoglobulin M antibodies at day 4 after transplantation in the serum of untreated and cyclosporine-treated Lewis recipients of cardiac xenografts, whereas a clear decrease occurred in anti-hamster immunoglobulin M antibody production during this period of time in the animals treated by combined immunosuppression. Inhibition of anti-donor immunoglobulin M antibody production, as evaluated by the direct enzyme-linked immunosorbent assay and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide measurements, extended for more than 100 days after transplantation in the combination therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1994

Prevention of orthotopic liver allograft rejection in rats with a short-term brequinar sodium therapy. Analysis of intragraft cytokine gene expression.

Brequinar sodium (BQR) is a new immunosuppressive drug that is highly effective in preventing graft rejection in several different experimental settings, including primary allografts and xenografts. A short course of BQR treatment during the onset of allograft rejection can induce the permanent survival of liver and kidney allografts in rats. To study the molecular basis of BQR-induced prolongation of allograft survival, we analyzed the intragraft pattern of IL-1 alpha, IL-2, IL-2R, IL-4, IL-6, IL-10, and TNF gene expression in the ACI-to-LEW liver allograft model. A semiquantitative polymerase chain reaction was developed to measure cytokine gene expression in control and BQR-treated liver graft recipients at various days after transplantation. Untreated control liver allografts expressed all of the cytokines analyzed. There was a marked increase in the steady state level of transcripts for each cytokine as graft rejection proceeded. The treatment of liver graft recipients with 12 mg/kg/day of BQR on days 6, 7, and 8 after transplantation suppressed the expression of all these cytokines within 24 hr of administration. The early suppression of cytokine expression was associated with a modest but distinct reduction in the infiltration of inflammatory cells into the liver grafts. The reduction in the level of transcripts for IL-4, IL-6, and IL-10 persisted in long-term survivors (30 days after transplantation). In contrast, there was a significant increase in the level of transcripts for IL-1 alpha, IL-2, and IL-2R in these long-term survivors. Our results demonstrated clearly that the pattern of cytokine gene expression during allograft rejection is significantly altered by a 3-day course of therapy with BQR. The temporary down-regulation of cytokine gene expression may be responsible for an altered immunological state that results in the prolonged survival of liver allografts.

Animals↗