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Biomedical subjects

M Garovoy

Publications and source records attributed to M Garovoy.

At least 19 recordsLinked to original sources
PubMed1997

A phase I trial of humanized anti-interleukin 2 receptor antibody in renal transplantation.

The efficacy of murine monoclonal anti-interleukin 2 alpha chain receptor (Tac) antibodies is limited by a short half-life and the development of antibodies to the heterologous protein. The safety, pharmacokinetics-dynamics, and immunosuppressive effect of a humanized anti-Tac antibody (HAT) was evaluated in 12 renal transplant recipients. Ten patients received living related transplants (three HLA-identical matches and seven one-haplotype or zero-haplotype matches) and two patients received cadaver organs. The patients were divided into four HAT treatment arms: 0.5 mg/kg/week (n=4), 1 mg/kg/week (n=2), 0.5 mg/kg every other week (n=3), and 1 mg/kg every other week (n=3). The first dose of HAT was given within 12 hr before transplantation, and four additional doses were given after transplantation. Patients were also placed on cyclosporine, steroids, and azathioprine. Only one patient, a recipient of a cadaver kidney in the lowest HAT treatment arm, had a reversible rejection episode. The 10 recipients of living related transplants were compared with 17 historical controls treated with an identical immunosuppressive regimen except for HAT. Whereas none of the HAT-treated living related donor recipients had a rejection episode, 6 of 17 (41%) of the historical controls had a rejection episode in the first year after transplantation. There were no first-dose reactions after HAT therapy or other subsequent side effects. None of the patients experienced opportunistic infections or malignancies. One patient developed low-titer anti-HAT antibodies, although the patient maintained high serum HAT concentrations throughout the study. Immune monitoring showed that there were no changes in the percentage or absolute counts of CD3 cells or T-cell subsets after HAT therapy. However, there was a significant decrease in the number of circulating lymphocytes that expressed free Tac. The overall harmonic mean half-life of HAT was 273 hr. The results of this study indicate that HAT given at 1 mg/kg every other week for a total of five doses may provide therapeutic HAT concentration levels and result in good saturation of Tac receptors for at least 12 weeks after transplantation. In summary, HAT is safe and is well tolerated by patients. Its long half-life and lack of immunization could make it a very useful immunosuppressive drug.

Adult↗
PubMed1996

Long-term engraftment following in utero T cell-depleted parental marrow transplantation into fetal rhesus monkeys.

A major concern with allogeneic BMT for treating most inherited diseases is the need to overcome graft rejection with conditioning chemotherapy which is associated with a relatively high morbidity and mortality. This can be eliminated if the transplant is done in utero when the fetus is unable to reject donor hematopoietic stem cells (HSC). We studied the efficacy of T cell-depleted (TCD) parental bone marrow as a source of HSC for transplantation into early gestation non-defective fetal rhesus monkeys. Thirteen opposite sexed TCD transplants were done into 44 day fetal recipients and 12 into 61 day recipients (165 day total gestation). The procedure-related mortality was 8%, all in the earlier age group. The overall survival was 60% at birth with a projected survival of 44 +/- 10% at 1.5 years with no difference between the two age groups. We used a PCR assay for the rhesus Y chromosome to detect male donor cells in female recipients (six animals transplanted at 44 days and five at 63 days). The overall engraftment rate was 73% with no difference as a function of gestational age at transplant. In six long-term surviving engrafted females we detected donor cells in the peripheral blood and bone marrow up to 3 years of age. We found a delay in the appearance of donor cells in the peripheral blood in engrafted animals, in some cases for up to 6 months post-BMT. In vitro mixed lymphocyte reaction and cell-mediated lymphocytotoxicity studies between the recipient and donor cells indicate that tolerance was induced to donor cells. Individual and pooled erythroid and myeloid marrow colonies grown in methyl cellulose were collected and analyzed for donor origin by PCR. The amount of donor cells in marrows from long-term engrafted animals was < 0.1%. In a fetal recipient studied at 35 days post-BMT, donor cells were detected in bone marrow and liver in both erythroid and myeloid lineages. These results indicate that TCD parental marrow can durably engraft in utero. While the engraftment rate is similar to that seen with fetal liver as the source of HSC, the degree of peripheral blood engraftment (percent donor cells) in this non-defective primate model is low. It will require increasing the percent pre-or postnatally for this approach to be clinically relevant in those disorders in which there is no selective survival advantage for normal engrafted donor cells.

Animals↗
PubMed1995

The OKT3 Antibody Response Study: a multicentre study of human anti-mouse antibody (HAMA) production following OKT3 use in solid organ transplantation.

Human anti-murine antibody titres following patient exposure to the monoclonal antibody Orthoclone OKT3 (muromonab-CD3) are determined by laboratories using diverse analytical methods which are not standardized and whose concordance is not established. A multicentre study group therefore compared testing for IgG anti-OKT3 antibody among seven laboratories. A set of 270 sera was obtained from 30 heart, 30 kidney and 30 liver transplant recipients with no previous exposure to OKT3 who were receiving OKT3 for induction immunosuppression. Sera were collected from each patient prior to and at 24 +/- 2 days and 31 +/- 2 days following initial OKT3 exposure. Identical aliquots of all 270 sera were tested for IgG anti-OKT3 antibody by each laboratory. In addition, the limit of detection of each laboratory's method was estimated by titration of an affinity-purified IgG anti-OKT3 reference material of known concentration. Anti-OKT3 antibody formation differed greatly among the three organ groups. Cardiac patients demonstrated the least sensitization and almost exclusively lower titres, while kidney recipients had more frequent and higher titre antibody formation. Liver recipients yielded the highest sensitization rate and the most frequent high titre sera. Importantly, the seven laboratories differed widely in the number of pretreatment sera reported as positive (ranging from 0% to 41% among laboratories), the number of post-OKT3 sera reported as positive (17-63%), the number of post-OKT3 samples with titre > or = 1000 (2-31%), and the number of patients sensitized 19-69%). Concordance among laboratories was highly variable, with interlaboratory agreement ranging from 38% to 83% on the sample titres assigned to 180 post-OKT3 sera. Many of the discordant results were consistent with differences in the limit of detection of the analytical methods, which ranged from 0.19 microgram/ml to > or = 15 micrograms/ml, a nearly 100-fold difference among laboratories. This study demonstrated the presence of both good concordance and significant discordance among laboratories in determining human anti-mouse antibody titres, and demonstrated that common titre categories (100, 1000, 10,000) were not equivalent among laboratories. The level of concordance among methods should be considered when comparing anti-OKT3 antibody results from different centres and their correlation with clinical events. Universal comparative testing, patterned after proficiency testing programmes, is needed to assess differences among laboratories and to bring uniformity and a sound interpretative basis to this field of testing.

Adult↗
PubMed1994

Anti-tetanus toxoid antibody production after mismatched T cell-depleted bone marrow transplantation.

We explored B-cell function after tetanus toxoid (TT) immunization in 12 children with severe combined immunodeficiency disease or leukemia who were long-term survivors of an HLA-matched sibling or haplocompatible T cell-depleted parental bone marrow transplant (BMT), 10 of their healthy donors, and 13 normal controls. Specific in vivo and in vitro anti-TT antibody (Ab) production were measured by ELISA. We studied donors' and recipients' peripheral blood mononuclear cells (PBMC) and mixed E- (non-T cells) and E+ cells (T cells) spontaneously and after stimulation by TT in the absence or presence of interleukin-2 (IL-2), IL-4, and IL-6. Five of the 12 patients and all donors and controls responded with in vivo anti-TT Ab. In vitro anti-TT Ab production correlated with the in vivo response. All seven of the nonresponders were either fully engrafted or mixed chimeras (donor T cells but autologous B cells and monocytes). We could not identify a T-cell defect in four of the five nonresponders who were tested. In contrast, E- cells from three of three responders cooperated with fresh donor E+ cells even when they shared only one HLA haplotype. In three of seven nonresponders, in vitro anti-TT Ab production was restored after the addition of IL-4 or IL-6 but not IL-2. Our results suggest that the humoral immunodeficiency that exists post mismatched T cell-depleted BMT is either a B-cell, a monocyte, or a B-cell/T-cell cooperation defect which, in some patients, may be correctible with the addition of a cytokine. Also, it is not necessary to engraft donor B cells to achieve normal antibody responses and the ability to respond does not appear to correlate with pretransplant chemotherapy.

Adolescent↗
PubMed1991

Activation of class I HLA expression by TNF-alpha and gamma-interferon is mediated through protein kinase C-dependent pathway in CML cell lines.

The combination of tumour necrosis factor alpha (TNF alpha) and gamma-interferon induced transcription of class I HLA genes in chronic myelogenous leukaemia (CML) cell lines through the formation of a complex between nuclear proteins and the transcriptional enhancers associated with these genes. Although gamma-interferon or TNF-alpha stimulated expression of class I HLA antigens in the EM2 and K562 CML cell lines when used alone, the effect of the combination of TNF-alpha and gamma-interferon was greater than that observed with either agent alone. The induction of class I HLA expression by gamma-interferon and TNF-alpha was inhibited completely by the isoquinoline sulfonamide H7, an inhibitor of protein kinase C. We conclude that the enhancement of the gamma-interferon induced transcriptional activation of class I HLA gene expression by TNF-alpha involves a protein kinase C-dependent pathway.

Base Sequence↗
PubMed1991

Graft vs. host disease after liver transplantation in humans: a report of four cases.

Four cases of patients in whom graft vs. host disease developed after liver transplantation are described. The clinical course of each patient was similar with fever, pancytopenia, diarrhea and a skin rash developing 1 or 2 mo after liver transplantation. The clinical diagnosis was made from skin or colon biopsy specimens. Liver dysfunction did not occur in the patients at the time of diagnosis. Extrahepatic donor DNA was identified in the three patients it was tested for. Three patients died from the complications of the disease primarily related to sepsis. The other patient recovered from the graft vs. host disease but died from lymphoproliferative disease.

Adult↗
PubMed1991

Improved results with combined donor-specific transfusion (DST) and sequential therapy protocol.

A combined DST-sequential CyA therapy protocol has been described that results in optimum graft survival for 1- and 2-haplotype mismatched living related donor-recipient combinations. In addition to the excellent graft survival obtained through 4 years, lower prednisone and CyA dosage levels are achieved with significantly decreased infection rates during the posttransplant period.

Blood Transfusion↗
PubMed1989

Inability of cyclosporine to completely prevent the recurrence of focal glomerulosclerosis after kidney transplantation.

From January 1984 through July 1986, 15 patients with biopsy-proven focal glomerulosclerosis (FGS) underwent kidney transplantation. Following transplantation, all patients were immunosuppressed with cyclosporine and prednisone. There were 8 men and 7 women with a mean age of 33 years (range, 16-47 years). Five patients (33%) had recurrence of FGS. Two patients had received kidneys from HLA identical siblings, and 3 patients were transplanted with cadaveric kidneys. In 4 out of 5 patients, the recurrence of FGS occurred within 3 months of transplantation. Of the 2 graft losses in this group, one was from recurrence of FGS. Ten patients followed for a mean of 25 months did not develop recurrence of FGS. No graft loss occurred in this group. Three patients with end-stage renal disease of unknown etiology were found to have FGS in the renal allograft and were presumed to have recurrence of FGS. All 3 patients developed the nephrotic syndrome following transplantation, and 1 patient has had progressive renal failure. Cyclosporine did not prevent the recurrence or the clinical manifestations of FGS following kidney transplantation. Additional studies are needed to determine if cyclosporine is effective in certain subgroups of patients with FGS.

Adolescent↗
PubMed1989

A poorly differentiated lymphoma of donor origin in a renal allograft recipient.

Malignant lymphoma is a frequent complication of organ transplantation. It has been suggested that such tumors arise as a result of uncontrolled proliferation of Epstein-Barr virus-infected B lymphocytes in an immunosuppressed host. Although a few cases of posttransplant lymphomas in bone marrow transplantation have been shown to be of donor cell origin, no recipients of solid-organ transplants are known to have developed lymphomas arising from donor cells. In this report, a case of diffuse high-grade lymphoma that apparently arose in the allograft of a renal transplant recipient is described. DNA fingerprinting demonstrated the tumor to be of donor origin; Epstein-Barr sequences were absent. A therapeutic trial consisting of withdrawal of immunosuppressive agents and administration of acyclovir was unsuccessful. These data support the notion that donor cells can undergo malignant transformation in solid-organ transplant recipients, and such tumors need not carry EBV genetic material.

Adolescent↗
PubMed1987

The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients.

212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random blood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. It is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.

Blood Transfusion↗