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Prevention of rejection and graft loss with an aggressive quadruple immunosuppressive therapy regimen in children and adolescents.

During the two-year period May 1991 to April 1993, 36 kidney transplants were performed in children less than 18 years of age at California Pacific Medical Center using an aggressive quadruple-therapy regimen of immunosuppression. The regimen consisted of induction with an antilymphocyte preparation (MALG in 21, OKT3 in 2, ATGAM in 12, none in 1), initial moderate-dose steroid therapy, early intravenous cyclosporine therapy, and azathioprine. Twenty living-related graft recipients were pretreated with donor-specific transfusions. Long-term cyclosporine was dosed by levels to keep through whole-blood levels (RIA) at 200-300 ng/ml. Twenty-five grafts were from living-related donors, two from living unrelated donors, and nine from cadaveric donors. Eleven (30%) recipients were five years old or under at the time of transplantation. Of these recipients 44% had complex congenital urologic disease and required urologic surgery prior to or at the time of transplantation. Patients have been followed for a mean of one year, with actual patient and graft survivals of 100% and 97%, respectively. Only one graft has been lost, to severe, early recurrent focal segmental glomerulosclerosis. Four of the 36 patients have had one rejection episode each, all reversed completely. Graft function is stable, with serum creatinine proportionate to age--mean serum creatinine in the children under two years old being 0.4 mg/dl, and in the adolescents 1.3 mg/dl, with two adolescent boys having the highest creatinine levels at 1.8 mg/dl. We conclude that an aggressive approach to immunosuppressive therapy in the early posttransplant period with MALG/OKT3/ATGAM induction and rapid achievement of therapeutic cyclosporine levels prevents rejection and results in excellent patient and graft survival with subsequent stable good graft function.

Adolescent↗

Positive pretransplant crossmatches predict early graft loss in liver allograft recipients.

We evaluated the influence of donor-recipient HLA compatibility and recipient pretransplant antidonor sensitization on liver allograft recipient survival. The overall graft survival results for 67 cyclosporine-prednisone treated liver allograft recipients at 3, 6, and 12 months posttransplant were 86%, 83%, and 83%, respectively. No significant differences were observed when comparing the one-year survivals of 81% vs. 85% for men and women or 80% vs. 85% for adult and pediatric patients. Similarly, no differences were observed when comparing one-year graft survivals for well vs. poorly matched recipients of 77% vs. 83% for recipients with < or = 2 HLA A, B vs. > 2 HLA A, B mismatches (MMs) and 82% vs. 82% for recipients with 0-1 HLA-DR MMs vs. 2 HLA-DR MMs, respectively. Pretransplant transfusion history and race also did not influence survival. Standard NIH (long-incubation) and anti-human globulin (AHG) crossmatches were performed. The 12% of recipients (8/67) displaying a positive NIH crossmatch experienced significantly poorer 3-, 6-, and 12-month survivals of 62% vs. 89%, 62% vs. 86%, and 62% vs. 86% (all P < 0.05), respectively, than the 59 NIH-crossmatch negative recipients. Similarly, the 16% (11/67) of recipients displaying a positive AHG crossmatch had significantly poorer 3-, 6-, and 12-month survivals of 63% vs. 91%, 54% vs. 89%, and 54% vs. 89% (all P < 0.05) respectively, than the 56 AHG crossmatch-negative recipients. NIH and AHG crossmatch-positive sera were treated with dithioerythritol (DTE) to establish whether reactivity was due to IgM or IgG immunoglobulin. One-year graft survivals of 65% vs. 30% (P < 0.05) were observed when the crossmatch-positive sera reactivities were due to IgM vs. IgG immunoglobulin. While graft survivals were improved when positive crossmatch serum reactivity was due to IgM, these survivals were still significantly poorer than when the crossmatches were completely negative (86% vs. 60%, P < 0.05 for NIH-negative vs. NIH-positive, but DTE-negative, and 88% vs. 77%, P < 0.05 for AHG-negative vs. AHG-positive, but DTE-negative). Therefore, an NIH- or AHG-positive crossmatch, due either to IgM or IgG reactivity, results in poor early (3- and 6-months) liver allograft survival. Crossmatch-positive recipients experienced significantly (P < 0.05) more rejections and more steroid-resistant rejections (P < 0.05) than crossmatch-negative recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

Redirection of T cell-mediated cytotoxicity by a recombinant single-chain Fv molecule.

We have produced two single-chain Fv (sFv) proteins by bacterial periplasmic secretion, one sFv with specificity for the hapten DNP, and the other for the human transferrin receptor. After solubilization and refolding, we recovered several mg of active sFv per liter of bacterial culture. Each sFv bound to cells bearing the appropriate Ag and could be used to direct targeted cellular cytotoxicity. Targeting relied on a universal bispecific antibody designed to cross-link CD3 on the cytotoxic T cell with a peptide fused to the sFv carboxyl-terminus. The universal bispecific antibody was used in combination with the Ag-specific sFv to redirect human cytotoxic T cells to kill a variety of target cells. Such an approach has a number of advantages that may make it useful for the immunotherapy of cancer and other diseases.

Amino Acid Sequence↗

[Pulmonary complications from monoclonal antibody (OKT3) immunosuppression in patients who have undergone an orthotopic liver transplant].

The authors investigated the incidence of pulmonary complications following immunosuppression with monoclonal antibodies (OKT3) in a series of 100 consecutive cases of orthotopic liver transplantation (OLT). Of 17 patients treated with OKT3 (16 for acute rejection and 1 for cyclosporine toxicity), 11 pulmonary infections were observed (65%), 9 of which (53%) with onset within a mean of 9 days after OKT3 administration. The infections were severe in all cases and lethal in 8 cases: the most common pathogens were Candida (4 cases) and Pseudomonas aeruginosa (3 cases). On the contrary, of 39 cases of rejection treated with steroids, infections were observed in 3 cases only (8%). The 53% incidence of pulmonary infections in OKT3 patients, significantly higher than in the extant patients (19%), confirms OKT3 treatment as a strong risk factor for severe pulmonary infections. Furthermore, the occurrence of pulmonary edema was directly related to OKT3 administration in 7 OKT3 patients (41%), whereas only 20 cases (24%) occurred in the extant OLT patients (p < 0.001). OKT3-related pulmonary edema was always observed in hyperhydrated patients at the time of drug administration and it seemed to be related to the vasoactive myocardiotoxic agents released by damaged T-cells.

Acute Disease↗

Coactivation with anti-CD28 monoclonal antibody enhances anti-CD3 monoclonal antibody-induced proliferation and IL-2 synthesis in T cells from autologous bone marrow transplant recipients.

Recent studies show that costimulation of T cells with anti-CD28 Mab (anti-CD28) enhances anti-CD3 Mab (anti-CD3)-induced proliferative responses and cytokine production. This study determines if coactivation with anti-CD3 and anti-CD28 corrects defects in proliferation and IL-2 secretion in peripheral blood lymphocytes (PBL) from bone marrow transplant (BMT) recipients. PBL or T cells from 5 of 16 autologous and 5 of 22 allogeneic recipients increased their anti-CD3-induced proliferation responses by > 50% after coactivation. In short-term (< 180 days after BMT) autologous recipients, the group mean response increased after anti-CD3 activation from 62,900 to 97,800 cpm after coactivation. In long-term (> 180 day after BMT) autologous recipients, the group mean response after anti-CD3 activation increased from 62,600 to 78,400 cpm after coactivation. The long-term autologous recipient group had costimulated responses from PBL that were significantly higher than the paired anti-CD3-induced responses (p < 0.01); in contrast, such differences were not seen in allogeneic recipient groups. After anti-CD3 stimulation, the mean response of 88,000 cpm for PBL from short-term allogeneic recipients and the mean response of 83,600 cpm for PBL from long-term allogeneic recipients were higher than those in PBL from autologous recipients were higher than those in PBL from autologous recipient groups. The amount of IL-2 secreted by T cells from three autologous and three allogeneic recipients was enhanced 0.9-25-fold by coactivation. Coactivation of PBL from selected recipients increased proliferation into the normal range and increased IL-2 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

OKT 3 reaction in a renal transplant patient.

In this case, the intended patient outcomes were achieved. Nursing was clearly able to take a very proactive role in providing the necessary emergency patient care to prevent further patient compromise. Once the immediate physiologic danger of respiratory decompensation was treated, nursing moved on to intervene in the less-serious complications associated with OKT 3 reaction to assure maximal patient comfort. Finally, patient teaching was done both to assess the learning needs associated with the OKT 3 reaction, as well as to prepare the patient and family for administration of additional doses of OKT 3. These nursing actions resulted in a very favorable outcome for both the patient and family.

Humans↗

Anti-CD3 and -CD4 monoclonal antibody in the treatment of steroid-resistant renal allograft rejection.

Between November 1987 and October 1991, 40 consecutive cadaveric renal recipients immunosuppressed with cyclosporine (CsA) who developed renal allograft rejection were treated with domestically prepared muromonab CD3 (Wu 338) and CD4 (Wu167). CD3 and CD4 monoclonal antibodies (McAb) as rescue treatment (n = 34) successfully reversed 29 cases of (85.3%) intractable renal allograft rejection (steroid resistant rejection 32 and anti-human thymocyte globulin [AHTG] resistant rejection 2) and completely reversed 4 cases of acute renal rejection episodes CD3 McAb as first-line treatment (n = 4). Two cases of chronic rejection failed in the treatment of McAb. Rejection episodes were reversed from 4 to 11 days (mean 6 days). Combined use of CD3 and CD4 McAb seemed to yield better results. Peripheral blood T lymphocyte subsets showed that CD3+, CD4+ and CD8+ decreased significantly after the treatment of McAb. No severe side-effects were observed in the treatment of McAb. The McAb could be administered safely. Pulmonary infection rate was 15%. The yearly graft survival rate was increased significantly (87.8% vs 80.0%).

Adult↗

Augmentation of NK cell activity and proliferation in cultured lymphocytes of leukemic patients by monoclonal antibodies CD3 and interleukin-2.

The aim of the present study was to induce NK cell activity in peripheral mononuclear cells (PMNC) of normal individuals or of leukemic patients. For this purpose, monoclonal antibodies (mAbs) anti-CD3 (MEM 57, OKT 3 and MEM 92), anti-CD59 (MEM 43) and anti-CD43 (MEM 59) were tested. MEM 43, MEM 59, MEM 57 and OKT 3 stimulated markedly the NK activity in fresh isolated PMNC of normal individuals, whereas the cytotoxicity in 3-day cultivated PMNC was enhanced only by MEM 57 and OKT 3. In comparison to interleukin-2 (IL-2), MEM 57 and OKT 3 induced less PMNC cytotoxicity but more cell proliferation. MEM 92 (anti-CD3, IgM) compared to MEM 57 or OKT 3 (anti-CD3, IgG) did not show any effect on both reactions mentioned above. PMNC of untreated leukemic patients exerted very negligible NK cell activity. Following 3-day culture of leukemic PMNC with OKT 3 or IL-2 the anti-K 562 cytotoxicity was markedly enhanced. In some cases the stimulating effect was more pronounced by IL-2, in others by OKT 3. Nevertheless, the best effect was gained in 7 out of 12 patients using a combination of IL-2 and OKT 3. On the other hand, OKT 3 did not synergize with IL-2 in normal PMNC culture.

Antibodies, Monoclonal↗