[Replacement of mycophenolate mofetil with azathioprine in patients with renal transplants]. / Zamena mikofenolat mofetila azatioprinom kod bolesnika sa presadjenim bubregom.

Numerous clinical studies demonstrated that mycophenolate mofetil (MMF) was significantly more effective in prevention of acute rejection episodes than azathioprine. Since the data supporting the long-term benefits of MMF therapy are not available, and considering the high cost of this therapy, we examined the safety of conversion from MMF to azathioprine in renal transplant patients. In 12 renal transplant patients (4 cadaveric and 8 living related donors) on triple immunosuppressive therapy (prednisone/MMF/cyclosporine) conversion from MMF to azathioprine was done after the first six to twelve post-transplant months. The majority of patients were in the low immunological risk of transplantation, and 7 (58.3%) received antithymocite globulin due to the delayed graft function. The mean follow-up period after the conversion to azathioprine was 6.4 months (range 3-12 months). Acute rejection episode was noticed only in one patient 8 months after the conversion following acute graft pyelonephritis. In all other patients graft function remained unchanged. We have concluded that the conversion from MMF to azathioprine in renal transplant patients on triple immunosuppressive therapy is safe and without detrimental effects on short-term allograft function. Long-term follow-up studies on larger number of patients are needed to confirm these observations.

[Use of mycophenolate mofetil in patients with a transplanted kidney and cyclosporin nephrotoxicity]. / Primena mikofenolat mofetila kod bolesnika sa presadjenim bubregom i ciklosporinskom nefrotoksicnoscu.

Cyclosporine (CsA) nephrotoxicity is an important problem in renal transplant recipients, which can influence long-term graft survival. The safety of conversion from CsA to azathioprine (AZA) remains controversial and can result in higher incidence of acute rejection. Mycophenolate mofetil (MMF) is a new immunosuppressive agent superior to AZA in the prevention of acute rejection. Five patients with cyclosporine nephrotoxicity were converted from CsA/AZA/prednisolon to MMF/prednisolon protocol. All patients had low immunological risk and 4 out of 5 patients received antithymocyte globulin before conversion as the induction therapy or as the treatment for acute rejection. Mean follow-up after conversion was 16.8 months (range 4-32 months). No patient experienced acute rejection during follow-up period. The mean serum creatinine concentration decreased from 219 +/- 44.18 (range 168-280) to 122.6 +/- 48.02 mumol/l (range 72-187 mumol/l) (p = 0.002). Arterial hypertension improved after CsA withdrawal in 20% of patients. We have concluded that, in selected patients with cyclosporine nephrotoxicity, CsA withdrawal with concomitant use of MMF is safe and effective in the improvement of graft function and arterial hypertension.

Peripheral blood granulocyte activity following contact sensitization of rats with dinitrochlorobenzene.

Contact hypersensitivity (CHS) reaction is a classic example of a cell-mediated reaction. As the afferent phase of the reaction includes inflammation, CHS is a suitable model for investigating non-specific immunity. Some aspects of granulocyte activity in the afferent phase of experimentally induced CHS to dinitrochlorobenzene (DNCB) in two genetically different rat strains, AO and DA were examined in this study. A shift in the ratio of granulocytes to lymphocytes in favour of granulocytes and an increase in granulocyte survival were noted in DA rats. Granulocytes from both strains demonstrated increased levels of NBT reduction and an increase in their adhesion to plastic. Decreased granulocyte adhesion in the presence of monoclonal antibodies to beta2 integrins (anti-CD11b/c and anti-CD18) points to the contribution of these molecules to granulocyte adhesiveness during the sensitization phase of CHS. Stimulation of adhesion in the presence of anti-CD11a antibody, points to a differential modulation of adhesion molecule activity during the afferent phase of CHS. Changes in functional activity of granulocytes demonstrated in this study might contribute to the development of CHS in rats.

[Outcome of kidney transplantation in patients on peritoneal dialysis]. / Ishod transplantacije bubrega kod bolesnika na peritoneumskoj dijalizi.

The initial experience suggested that kidney transplantation could be hazardous for patients on peritoneal dialysis due to the high risk of peritonitis and a possible high incidence of acute rejection. In this paper we have presented our experience with kidney transplantation in these patients. During the last four years kidney transplantation was performed in 9 patients on peritoneal dialysis. The average time spent on peritoneal dialysis was 20.6 +/- 7.6 months. In all patients peritoneal catheter was removed during the surgery. During the posttransplantation period a triple immunosuppressive therapy including steroids, cyclosporin and azathioprineor mycophenolate mofetil was administered in all patients. In comparison to patients on hemodialysis no significant difference in the incidence of acute rejection episodes, delayed graft function, graft arterial thrombosis and graft function recovery was observed. Patients on peritoneal dialysis had significantly greater and longer wound drainage in comparison to patients on hemodialysis. It was concluded that peritoneal dialysis had no negative influence on short-term outcome of kidney transplantation.

[Importance of determining the absolute CD3+ lymphocyte count during induction therapy with antithymocyte globulin in kidney transplantation patients]. / Znacaj odredjivanja apsolutnog broja CD3+ limfocita tokom indukcione terapije antitimocitnim globulinom kod bolesnika sa transplantovanim bubregom.

Antithymocyte globulin (ATG) is successfully applied in prophylaxis and treatment of renal allograft rejection. However, it is an expensive mode of therapy, associated with increased risk of opportunistic infections and lymphoproliferative diseases. For this reason, monitoring of ATG immunosuppressive effects as well as individual dose adjustment represent an important therapeutic approach. Here we report our results of ATG dose titration according to total lymphocyte count (< 300/microliter) and absolute CD3+ count (< 50/microliter) in seven renal transplant patients. Monitoring of absolute CD3+ count enabled reduction of the mean daily dose from the recommended dosage in all patients. Our results have also shown that the absolute CD3+ count is a more reliable parameter than the total lymphocyte count for monitoring of ATG biological effects on T cells. When rapid, significant and stable decrease of absolute CD3+ count is reached, ATG dose can be further adjusted according to the total lymphocyte count. With this approach, ATG treatment becomes rational and safe, with well established immunosuppressive effect, reduced risk of overimmunosuppression and considerable cost benefit.

Differential effects of anti-rat CD11b monoclonal antibodies on granulocyte adhesiveness.

Four different monoclonal antibodies (mAbs) reactive with rat CD11b (ED7, ED8, OX-42 and 1B6c) have been characterized for their ability to induce homotypic aggregation of granulocytes or to modify granulocyte adhesiveness triggered by phorbol myristate acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP). Cross-blocking experiments showed that these mAbs recognize at least three different epitopes on CD11b. OX-42 mAb recognizes an inhibitory epitope since the mAb inhibited homotypic aggregation of granulocytes and their adherence to plastic in the presence of PMA or fMLP. ED7 and ED8 induced homotypic aggregation of granulocytes which was blocked by OX-42 and anti-CD18 mAb (WT3) suggesting that CR3 itself is involved in the adhesion process. The aggregation was dependent on active cell metabolism, intact cytoskeleton, divalent cations and activation of tyrosine kinases sensitive to genistein. Staurosporine, okadaic acid and orthovanadate potentiated the aggregation. ED7 and ED8 potentiated homotypic aggregation and adhesion of granulocytes to plastic caused by fMLP, but inhibited granulocyte adhesion to plastic induced by PMA. 1B6c recognizes an epitope that transmits a proaggregatory signal upon binding of the mAb but only if the granulocytes are in contact with plastic or are activated by fMLP. In contrast, 1B6c inhibited granulocyte adhesion to plastic triggered by PMA or fMLP. These data suggest the existence of functionally different epitopes on rat CD11b and indicate that some anti-CD11b mAbs are able to functionally activate CR3.

[Cyclosporin A in the treatment of Behçet's disease]. / Primena ciklosporina A u lecenju Behçet-ove bolesti.

The results of Cyclosporin A treatment of 15 patients with Behçet's disease were examined in the study--9 females (aged from 32 to 34 years, mean 33 years) and 12 males (aged from 25 to 55 years, approximately 34.33 years). Among them, the majority were with chorioretinitis (10/15 or 66.6%). Besides chorioretinitis two patients were simultaneously with iridocyclltis, while in three the whole nervous system was affected (meningoencephalitis, simultaneously pyramidal syndrome with the signs of extrapyramidal lesion and consciousness disorder in one patient). In one patient myocarditis was revealed, and the one was with deep aphtous ulcer. The approximate daily dose was 5 mg/kg in 13 patients, and 7.5 mg/kg/d in 2 patients. For that, the level of the drug in blood elevated from 79 to 380 ng/ml, approximately 170 ng/ml. The effect was favourable in 12 patients (complete restraint of the disease evolution), partial in 2 patients (slowing of the disease course) while it was incomplete in one patient for the interruption of the therapy 15 days after its beginning.

Increased activity of lymph node cells in thermal injury.

While trauma-induced suppression of T-cell responses is well documented, only few studies address lymphocyte activation. The aim of this study was to investigate the functional activity of lymph node cells in rats subjected to scald injury, proliferative activity, cytokine production, and responsiveness to exogenously added cytokines was evaluated in cells from lymph nodes draining burned tissue and from distant, nondraining lymph node cells. Results presented clearly show that lymph node cells in scalded rats are activated in vivo although the extent of proliferation and pattern of cytokine production differ: a) proliferative activity was elevated both in draining and distant lymph nodes, but was more pronounced in cells from lymph nodes draining the injured region; b) increased production of IL-2, and particularly IL-1 and IL-6 was found and coincides well with peak of proliferative activity of draining lymph node cells; IL-2 production by distant lymph node cells remained unchanged, IL-1 and IL-6 production was significantly increased coinciding with increased proliferation; c) increased responsiveness to exogenously supplied cytokines was found in draining lymph node cells, while it remained unchanged in nondraining lymph node cells. Early activation of lymphocytes demonstrated in our experiments could be one of the previously unrecognized consequences of trauma-induced immunosuppression.