Massive pleural endometriosis.

We present a patient who was referred to our thoracic surgical service with a massive, loculated right pleural effusion accompanied by significant ascites. Thoracotomy and decortication were required and pleural biopsy led to a diagnosis of endometriosis. Aggressive medical therapy was subsequently initiated but hysterectomy with bilateral oophorectomy was required due to poor symptom control and the inability to rule out a neoplastic process. There are less than 15 reported cases of endometriosis presenting with both pleural effusion and ascites. Thoracic surgeons presented with such a scenario should be cognizant of this pathological entity.

Allo-tolerance and allorejection responses ex vivo.

Spleen cells from fully immune competent mice show different intracellular STAT responses to alloantigen. Cells from mice primed to accept the alloantigen have low STAT 6 and fragmented STAT 4, compared to cells from mice primed to reject the same alloantigen.

Comparison between tacrolimus and cyclosporine as immunosuppressive agents compatible with tolerance induction by CD4/CD8 blockade.

BACKGROUND: Donor-specific tolerance can be induced in mice by transient antibody blockade of the CD4 and CD8 co-receptors of T cells. To evaluate the potential application of CD4/CD8 blockade in the clinic, we have asked if either tacrolimus or cyclosporine counteract the tolerogenic process. METHODS: Using the fully mismatched mouse cervical heart transplant model, BALB/c (H2d) to CBA (H2k), the experimental groups were (i) no therapy, (ii) tacrolimus (1 mg/kg, i.p., daily, days 0-14); (iii) cyclosporine (25 mg/kg, i.p., daily, days 0-14), (iv) blocking monoclonal antibodies (mAbs) to CD4 and CD8 (2 mg, i.p., starting day 0 and on alternating days thereafter for a total of six doses), (v) tacrolimus plus mAbs, and (vi) cyclosporine plus mAbs. RESULTS: Allograft survival was prolonged in both the tacrolimus and cyclosporine groups. mAbs alone induced tolerance, and mAbs combined with tacrolimus also induced tolerance. In contrast, the combination of mAbs and cyclosporine was toxic. CONCLUSIONS: The induction of tolerance by blocking CD4 and CD8 was not prevented by tacrolimus. However, combination of cyclosporine with the same tolerogenic protocol was toxic to mice.

STAT 6 up-regulation by FK506 in the presence of interleukin-4.

BACKGROUND: FK506 perturbs normal phosphorylation by inhibition of the PP2B protein phosphatase, calcineurin. Calcineurin activity is required for intracellular signal transduction via the T cell receptor that in turn leads to either TH1, or TH2, -type responses to antigen. This choice of response involves differential phosphorylation of STATS (Signal Transducers and Activators of Transcription) for induction of STAT activity. Interferon-gamma activates STAT1, a TH1-type mediator, and interleukin-4 activates STAT6, a TH2-type mediator. We ask if FK506 biases STAT activation toward a TH2-type response. METHODS: Cells of the RAW 264.7 mouse macrophage line were treated with interleukin-4, or interferon-gamma, plus or minus FK506, and any effect on STAT6 and STAT1 was compared. RESULTS: Interleukin-4 specifically induced activation of STAT6, and pretreatment with FK506 enhanced this activity. Interferon-y induced STAT1 activity but this was not influenced by FK506 pretreatment. CONCLUSION: FK506 protects against allograft rejection by inhibiting interleukin-2 production. Such protection may be enhanced by FK506-mediated up-regulation of STAT6 activity.

Prope tolerance with induction using Campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients.

The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients.

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.

Potential for improved therapeutic index of FK506 in liposomal formulation demonstrated in a mouse cardiac allograft model.

BACKGROUND: FK506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue immunosuppressive agent. Despite these benefits, the potential value of FK506 is limited by toxic side effects that result in a narrow therapeutic index. By encapsulating the active drug within liposomes (LipoFK506), a new formulation has been developed that might improve this therapeutic index. METHODS: The biodistribution of tritiated-FK506 administered i.v. showed that the drug remained associated with the liposomal carrier in vivo, and that its tissue distribution was increased in heart and spleen compared to nonliposomal FK506. The immunosuppressive efficacy of lipoFK506 compared with conventional FK506 formulation was tested in vivo. CBA (H2k) mice were engrafted with BALB/c (H2d) mouse hearts with daily immunosuppression using either 1 mg/kg FK506, or 1 mg/kg LipoFK506, from day 0 to 14. RESULTS: At day 7 the blood trough level of FK506 in the FK506 group was 10-fold higher (25 microg/L) than that in the LipoFK506 group. In both groups the median heart allograft survival was similar at around 26 days. The possibility that FK506, or LipoFK506, might influence antibody-mediated tolerogenesis was addressed in the same model: neither formulation prevented tolerance induction by CD4 and CD8 blockade. CONCLUSION: LipoFK506 is a novel formulation of FK506 that is efficacious at low blood trough FK506 levels. This property has a direct potential benefit for clinical organ transplantation.