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T Gooley

Publications and source records attributed to T Gooley.

At least 19 recordsLinked to original sources
PubMed2001

Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.

BACKGROUND: Successful engraftment of hematopoietic stem cells from unrelated donors is influenced by disparities between the donor and recipient for HLA-A, B, and C alleles. Disparities between HLA sequence polymorphisms that are serologically detectable are termed antigen mismatches, whereas those that can be identified only by DNA-based typing methods are termed allele mismatches. Whether both kinds of polymorphisms are important in transplantation is not known. We tested the hypothesis that allele mismatches that are detectable only at the DNA level are less immunogenic than those that are serologically detectable and thereby are associated with a lower risk of graft failure after hematopoietic-cell transplantation METHODS: We used DNA sequencing to define the HLA-A, B, and C alleles in 471 patients who received bone marrow from unrelated donors for the treatment of chronic myeloid leukemia after myeloablative conditioning therapy. The odds ratios for graft failure were determined for recipients of transplants from donors with a single class I allele mismatch, a single class I antigen mismatch, or two or more class I mismatches, as compared with those with no mismatch RESULTS: A single HLA allele mismatch did not increase the risk of graft failure, whereas a single antigen mismatch significantly increased the risk. The risk was also increased if the recipient was HLA homozygous at the mismatched class I locus or if the donor had two or more class I mismatches CONCLUSIONS: HLA class I antigen mismatches that are serologically detectable confer an enhanced risk of graft failure after hematopoietic-cell transplantation. Transplants from donors with a single class I allele mismatch that is not serologically detectable may be used without an increased risk of graft failure.

Genes, MHC Class I↗
PubMed2001

Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings.

Red blood cell (RBC) and platelet transfusion requirements in patients given nonmyeloablative versus conventional peripheral blood stem cell (PBSC) transplants from HLA-matched siblings were compared. Between December 1997 and March 2000, 40 patients, aged 21 to 67 years (median 51), with hematologic malignancies underwent nonmyeloablative allografts after either 2 Gy total body irradiation alone (n = 30) or 2 Gy total body irradiation preceded by fludarabine 30 mg/m(2)/d on days -4, -3, and -2 (n = 10). All received postgrafting mycophenolate mofetil and cyclosporine. Controls included 67 concurrent patients, aged 23 to 66 years (median, 46 years), given conventional PBSC transplants following high-dose conditioning and postgrafting methotrexate and cyclosporine. Among patients given nonmyeloablative transplants, 23% required platelet transfusions compared with 100% among patients given conventional grafts (P <.0001). Further, the number of platelet units given to nonmyeloablative recipients was reduced, with a median of 0 (range, 0 to 214) compared with a median of 24 (range, 4 to 358) after conventional transplantation (P <.0001). Sixty-three percent of nonmyeloablative recipients required RBC transfusions compared with 96% of those with conventional grafts (P =.0001). The number of RBC units transfused was also reduced, with a median of 2 (range, 0 to 50) compared with 6 (range, 0 to 34) after conventional transplantation (P =.0001). High transfusion requirements before transplantation and donor-recipient ABO incompatibility increased transfusion requirements in both patient groups, though neither significantly influenced the outcome of the analysis. Neither patient age, splenomegaly at transplantation, development of graft-versus-host disease, nor posttransplantation cytomegalovirus antigenemia or cytomegalovirus disease had statistically significant influences on posttransplantation transfusions.

Adult↗
PubMed2001

Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial.

This study compared the incidence of clinical extensive chronic graft-versus-host disease (GVHD), transplantation-related mortality, survival, and relapse-free survival among recipients randomly assigned to receive a 24-month or a 6-month course of cyclosporine prophylaxis after transplantation of allogeneic marrow from an HLA-identical sibling or alternative donor. Patients who did not have clinical manifestations of chronic GVHD on day 80 after transplantation were eligible for the study if they previously had acute GVHD or if a skin biopsy showed histologic evidence of chronic GVHD. Clinical extensive chronic GVHD developed in 35 of the 89 patients (39%) in the 24-month group and 37 of the 73 patients (51%) in the 6-month group. The hazard of developing chronic GVHD was not significantly different in the 2 groups (hazard ratio = 0.76; 95% confidence interval, 0.48-1.21; P =.25). In addition, there were no significant differences between the 2 groups in transplantation-related mortality, survival, or disease-free survival.

Adult↗
PubMed2001

CD34 cell dose in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation.

A retrospective analysis of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cell (G-PBMC) products harvested from healthy donors indicates significant variability in both the absolute number and relative proportion of CD34, CD3, and CD14 cells obtained. This report examined whether variations in the cellular composition of G-PBMC products correlated with clinical outcomes after myeloablative allogeneic transplantation. The numbers of CD34, CD3, and CD14 cells infused into 181 human leukocyte antigen (HLA)-identical sibling recipients were analyzed with respect to tempo of engraftment, acute graft-versus-host-disease (GVHD), clinical extensive chronic GVHD, overall survival, and disease relapse. Neither acute GVHD, overall survival, nor disease relapse was statistically significantly associated with CD34, CD3, or CD14 cell doses or the CD14 to CD3 ratio. CD3 and CD14 cell doses and CD14 to CD3 ratios did not correlate with the tempo of neutrophil and platelet engraftment. However, increasing CD34 cell numbers were significantly associated with accelerated neutrophil (P =.03) and platelet (P =.01) engraftment. Higher doses of CD34 cells (> 8.0 x 10(6)/kg) were also associated with a significantly increased hazard of clinical extensive chronic GVHD (HR = 2.3, 95% confidence interval [CI] 1.4-3.7, P =.001), but neither CD3 nor CD14 doses were statistically significantly associated with chronic GVHD. It was concluded that CD34 cell dose in G-PBMC grafts appears to affect both the engraftment kinetics and the development of clinical extensive chronic GVHD in HLA-identical sibling recipients but without a demonstrable impact on survival, relapse, and acute GVHD. Given the morbidity associated with extensive chronic GVHD, efforts to further accelerate engraftment in HLA-matched sibling transplants by increasing CD34 cell number in G-PBMC products may be counterproductive.

Acute Disease↗
PubMed2001

Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes.

Genetically modified donor T cells with an inducible "suicide" gene have the potential to improve the safety and availability of allogeneic hematopoietic stem cell transplantation by enhancing engraftment and permitting control of graft-versus-host disease (GVHD). However, several clinical studies of gene-modified T cells have shown limited to no in vivo function of the ex vivo expanded T cells. Using the well-established dog model of allogeneic marrow transplantation, the question was asked if retrovirally transduced, donor derived, ex vivo expanded cytotoxic T lymphocytes (CTLs) that are recipient specific could enhance engraftment of dog leukocyte antigen (DLA)-haploidentical marrow following a single dose of 9.2 Gy total body irradiation and no postgrafting immunosuppression. In this setting, only 4 of 11 control recipients of DLA-haploidentical marrow without added CTLs engrafted. CTLs did not enhance engraftment of CD34(+) selected peripheral blood stem cells. However, recipient-specific CTLs enhanced engraftment of DLA-haploidentical marrow in 9 of 11 evaluable recipients (P =.049). All dogs that engrafted developed multiorgan GVHD. To facilitate in vivo tracking, 8 dogs received CTLs transduced with a retroviral vector encoding green fluorescent protein (GFP) and neomycin phosphotransferase (neo). Recipients that engrafted had sharp increases in the numbers of circulating GFP(+) CTLs on days +5 to +6 after transplantation. GFP(+) CTLs isolated from blood were capable of recipient-specific lysis. At necropsy, up to 7.1% of CD3(+) cells in tissues were GFP(+) and polymerase chain reaction in situ hybridization for neo showed infiltration of transduced CTLs in GVHD-affected organs. These results show that ex vivo expanded, transduced T cells maintained in vivo function and enhanced marrow engraftment.

Animals↗
PubMed2001

The significance of bcr-abl molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation.

The bcr-abl chimeric messenger RNA is frequently detected in chronic myeloid leukemia (CML) patients after bone marrow transplantation. It was previously reported that the relapse risk of bcr-abl detection 6 to 12 months after transplantation was greater than 40%. This risk decreased as the time between transplantation and detection increased. To further define the relapse risk associated with bcr-abl molecular detection in "late" CML survivors, 379 consecutive CML patients alive at 18 months after transplantation or later were studied. Ninety of 379 patients (24%) had at least one positive bcr-abl test 18 months after transplantation or later; 13 of 90 bcr-abl-positive patients (14%) and 3 of 289 bcr-abl-negative patients (1.0%) relapsed. The median time from bcr-abl detection to relapse was 916 days (range, 251-2654 days). The hazard ratio of relapse associated with bcr-abl detection was 19.2 (P <.0001). The stage of disease, chronic graft-versus-host disease, and the donor type did not alter the association between bcr-abl and relapse. Quantification of bcr-abl was performed on 344 samples from 85 bcr-abl-positive patients by means of a real-time quantitative reverse transcriptase-polymerase chain reaction assay. The median bcr-abl change of patients who relapsed was significantly greater than those that remained in remission (P =.002). The median bcr-abl level at relapse was 40 443 bcr-abl copies per microg RNA (range, 960-299 552). Of 73 bcr-abl-positive patients who failed to relapse, 69% had only one positive test at a median of 24 copies bcr-abl per microg RNA. The detection of bcr-abl is common following transplantation. The prognostic significance of a qualitative bcr-abl can be refined by quantitative assays and thus may target patients who would benefit from early intervention.

Adolescent↗
PubMed2001

Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome.

Parainfluenza virus (PIV) infections may be significant causes of morbidity and mortality in patients undergoing stem cell transplantation, but data regarding their impact on transplant-related mortality is limited. This study sought to determine the risk factors of PIV acquisition and progression to lower respiratory tract infection, their impact on transplant-related mortality, and the effectiveness of antiviral therapy. A total of 3577 recipients of hematopoietic stem cell transplantation (HSCT) between 1990 and 1999 were studied. PIV infections occurred in 253 patients (7.1%); 78% of these infections were community acquired. Multivariable analysis identified the receipt of an unrelated transplant as the only risk factor for PIV acquisition; the dose of corticosteroids at the time of PIV infection acquisition was the primary factor associated with the development of PIV-3 pneumonia, both among allogeneic and autologous HSCT recipients. Both PIV-3 upper respiratory infection and pneumonia were associated with overall mortality. Pulmonary copathogens were isolated from 29 patients (53%) with pneumonia. Mortality was highly influenced by the presence of copathogens and the need for mechanical ventilation. Aerosolized ribavirin with or without intravenous immunoglobulin did not appear to alter mortality from PIV-3 pneumonia, nor did such therapy decrease the duration of viral shedding from the nasopharynx among patients with pneumonia. Corticosteroid administration thus drives the development of PIV pneumonia in a dose-dependent fashion, even among autologous HSCT recipients. Both upper and lower tract PIV infections are predictors of mortality after HSCT. Currently available antiviral therapy appears to be inadequate in reducing viral shedding or mortality once pneumonia is established. (Blood. 2001;98:573-578)

Adolescent↗
PubMed2001

Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes.

To determine the risk factors and outcomes associated with rising cytomegalovirus (CMV) antigenemia levels during preemptive therapy among stem cell allograft recipients, 119 patients with CMV antigenemia were studied. Patients were prospectively monitored for CMV antigenemia weekly; those with positive findings on antigenemia tests were treated with intravenous ganciclovir (5 mg/kg twice daily for 1 week, followed by 5 mg/kg per day for 5-6 d/wk). While on therapy, 47 of 119 (39%) patients demonstrated increases that were 2 or more times greater than their baseline values, whereas 33 of 119 (28%) patients demonstrated increases that were 5 or more times greater. Rising antigenemia was confirmed by polymerase chain reaction for CMV DNA. Multivariate analysis identified corticosteroids as the primary risk factor for increasing antigenemia: for increases greater than or equal to twice the baseline, 1 to 2 mg/kg steroids was associated with an odds ratio (OR) of 4.0. For increases greater than or equal to 2 mg/kg steroids, the OR was 10.1. CMV isolates obtained at the time of rising antigenemia were susceptible to ganciclovir, indicating that resistance was not a major factor. Overall, rising antigenemia levels were not correlated with CMV disease. All 4 patients in whom CMV disease developed during therapy, however, had rising antigenemia levels. Among the 47 patients with antigenemia increases greater than or equal to twice the baseline, 15 were re-induced with antivirals, whereas 32 continued to receive maintenance therapy. All 4 patients in whom CMV disease developed during therapy received maintenance therapy, and 3 died with CMV disease. Thus, host factors such as the receipt of corticosteroids explain increasing viral load during the early phase of preemptive therapy. Continued induction dosing or re-induction may protect against early breakthrough CMV disease and CMV-related death among patients with rising antigenemia on preemptive therapy. (Blood. 2001;97:867-874)

Adolescent↗
PubMed2001

Hypocalcemia: a pervasive metabolic abnormality in the critically ill.

Hypocalcemia has been reported in critically ill patients, most commonly in association with sepsis syndrome. However, the severity and incidence of hypocalcemia in nonseptic but critically ill patients has not been well defined. Therefore, the goal of this study was to identify and compare the frequency and degree of hypocalcemia in critically ill patients with differing underlying illnesses (those admitted to medical, surgical, trauma, neurosurgical, burn, respiratory, and coronary intensive care units [ICUs]; group A; n = 99). Results were compared with the frequency and degree of hypocalcemia in non-critically ill ICU patients (initially admitted to an ICU but discharged within 48 hours; group B; n = 50) or hospitalized non-ICU patients (group C; n = 50). Incidences of hypocalcemia (ionized calcium [Ca] < 1.16 mmol/L [less than normal]) were 88%, 66%, and 26% for groups A, B, and C, respectively (P: < 0.001). In group A, the frequency of hypocalcemia did not depend on the ICU setting or presence of sepsis. However, the occurrence of hypocalcemia correlated with both Acute Physiology and Chronic Health Evaluation II score (r = -0.39; P: < 0.001) and patient mortality (eg, hazard ratio for death, 1.65 for Ca decrements of 0.1 mmol/L; P: < 0.002). Hypomagnesemia, number of blood transfusions, and presence of acute renal failure were each associated with depressed Ca levels. A weak association (r = -0.12; P: = 0.09) was noted between serum Ca level and QT interval. Clinical concern stemming from hypocalcemia was underscored by the substantial use of intravenous (IV) Ca therapy ( approximately 2 to 3 g IV). We conclude that hypocalcemia is extremely common in hospitalized patients (up to 88%) and correlates with severity of illness, but not with a specific illness per se. Whether it directly impacts patient survival remains unknown. Resolution of this issue appears to be critical because of the frequency with which it leads to high-dose IV Ca therapy.

APACHE↗
PubMed2001

Trafficking of CD34+ cells into the peripheral circulation during collection of peripheral blood stem cells by apheresis.

The number of CD34+ cells collected during apheresis is related to the volume of blood processed. In large-volume apheresis (LVL) procedure, more cells can be collected than were originally present in the peripheral blood at the start of the collection procedure. We prospectively studied the levels of CD34+ cells in the blood and apheresis product during LVL procedures for 21 patients with acute myelogenous leukemia or multiple myeloma. These patients experienced a slow decline in blood CD34+ cell concentrations during the apheresis procedure. No patient demonstrated a sustained rise in CD34+ cell counts as a result of the procedure. The number of CD34+ cells collected exceeded the number calculated to be in the peripheral blood at the start of the procedure by an average of 3.0-fold. The efficiency of collection for CD34+ cells averaged 92.6% and did not vary with speed of blood processing, diagnosis, or mobilization regimen. The calculated release of CD34+ cells from other reservoirs into the peripheral blood averaged 3.71 x 10(6)/min (range, 0.36-13.7 x 10(6)/min), and correlated (r = 0.82) with the concentration of these cells in the peripheral blood at the start of the procedure. These data show that the apheresis procedure used in this study does not affect the release of CD34+ cells in a cytokine-treated patient. LVL will result in collection of larger quantities of CD34+ cells than procedures involving processing of smaller volumes of blood, but the number of cells collected is limited by the rate of release of these cells into the peripheral circulation where they are accessible for collection.

Acute Disease↗
PubMed2001

Haemopoietic stem cell transplantation for advanced polycythaemia vera or essential thrombocythaemia.

Ten patients with polycythaemia vera (PV) and nine with essential thrombocythaemia (ET) received a haemopoietic stem cell transplant (HSCT) at the Fred Hutchinson Cancer Research Center between May 1988 and March 2000. HSCT was performed because of progression to the spent phase of the disease with myelofibrosis and splenomegaly in 10 patients and evolution into a myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML) in nine patients. Patients were 18-59 years old (median 43). The interval from diagnosis to HSCT was 77-300 months (median 170). Seven patients were splenectomized before transplantation, and all but five had been treated with cytotoxic agents. Eleven patients received a transplant from a related, and eight from an unrelated, donor following conditioning with chemotherapy only or chemotherapy plus total body irradiation regimens. All evaluable patients achieved sustained engraftment. Twelve patients are surviving 5-116 months (median 41) after transplant, 10 in continued complete remission, one in haematological remission with residual marrow fibrosis and one with mixed haemopoietic chimaerism currently receiving therapy with interferon. Seven patients (six with AML/MDS and one with myelofibrosis) died of transplant-related complications. These data show that HSCT can provide curative therapy for patients with PV and ET with advanced disease.

Adult↗
PubMed2001

The biological significance of HLA-DP gene variation in haematopoietic cell transplantation.

Although it has been over 25 years since HLA-DP was mapped to the major histocompatibility complex (MHC), its biological functions remain ill-defined. We sought to test the hypothesis that HLA-DP functions in a manner similar to that of other class II genes by measuring the risk of clinically severe grades III-IV acute graft-vs.-host disease (GVHD) associated with recipient HLA-DP disparity after haematopoietic cell transplantation. HLA-DPB1 exon 2 was sequenced in 205 patients who underwent transplantation from HLA-A, -B, -C, -DRB1 and -DQB1 allele-matched unrelated donors. HLA-DPB1 mismatched recipients experienced a significantly increased risk of acute GVHD compared with HLA-DP-identical transplants. Patients who were mismatched for a single HLA-DPB1 allele had an odds ratio (OR) of 1.0 (0.5, 2.2; P = 0.99) and patients who were mismatched for two alleles had an OR of 2.2 (1.0, 4.9; P = 0.06) for developing acute GVHD. Compared with matched and single-allele mismatched transplants, patients who were mismatched for two DPB1 alleles had an OR of 2.2 (1.2, 4.1; P = 0.01). HLA-DP plays an important role in the alloimmune response. A threshold effect of multiple HLA-DP disparities is evident in determining the risk of acute GVHD after haematopoietic cell transplantation from unrelated donors.

Adolescent↗
PubMed2001

Secondary failure of platelet recovery after hematopoietic stem cell transplantation.

After primary recovery of platelet counts after transplantation, there can be a late persistent decline called secondary failure of platelet recovery (SFPR), which may occur although the counts of other cell lineages remain within the normal range. SFPR was defined as a decline of platelet counts below 20,000/microL for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts > or = 50,000/microL without transfusions for 7 consecutive days after hematopoietic stem cell transplantation (HSCT). The study population consisted of 2871 consecutive patients receiving transplants from January 1990 to March 1997. After primary recovery of platelet counts, SFPR not due to relapse of the underlying disease was observed in 285 of 1401 (20%) patients undergoing allogeneic transplantation and 36 (8%) of 444 patients undergoing autologous transplantation, with a median time of onset after transplantation at day 63 (range, day 21-156) and day 44 (range, day 24-89), respectively. Concomitant neutropenia was seen in 57 (20%) of 285 patients undergoing allogeneic HSCT and 7 (19%) of 36 patients undergoing autologous HSCT with SFPR. By multivariable analysis, the following were factors significantly associated with SFPR after allogeneic HSCT: a transplant from an unrelated donor; a graft-versus-host disease (GVHD) prophylaxis other than methotrexate and cyclosporine; development of grade 2 through 4 acute GVHD; impaired renal or liver function; conditioning with the combination of busulfan, cyclophosphamide, and total body irradiation; stem cell dose; and infections. Cytomegalovirus infection after engraftment and source of stem cells were the only significant risk factors after autologous HSCT. The hazard rate of death was significantly higher in patients who experienced SFPR (hazard ratio = 2.6 for allogeneic HSCT; hazard ratio = 2.2 for autologous HSCT). SFPR was associated with serious complications and poor outcome after transplantation. The identification of the characteristics and risk factors for SFPR could improve patient counseling and management and lead to the design of effective treatment strategies.

Adolescent↗
PubMed2001

Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation.

Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.

Bacteremia↗
PubMed2001

Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience.

Community respiratory viruses (CRVs) are an important cause of morbidity and mortality among recipients of hematopoietic stem cell transplants (HSCT). At the Fred Hutchinson Cancer Research Center, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) infections in HSCT recipients have been studied intensively for more than a decade. Over time, mortality from these infections has declined as the approach to diagnosis has become more aggressive and more stringent preventive measures have been instituted. However, mortality among HSCT recipients with RSV or PIV pneumonia remains high. Uncontrolled studies at our center suggest that prompt therapy with aerosolized ribavirin has reduced mortality from RSV pneumonia but does not appear to affect the course of established PIV pneumonia. Two controlled clinical trials of ribavirin therapy for RSV infection in HSCT recipients are in progress.

Clinical Trials as Topic↗
PubMed2000

Non-Fc receptor-binding humanized anti-CD3 antibodies induce apoptosis of activated human T cells.

Human trials in organ allografts have demonstrated that murine anti-CD3 mAbs are immunosuppressive. By mimicking Ag, anti-CD3 can produce T cell activation, anergy, or death. Activation of resting T cells in vivo results in dose-limiting cytokine release and is caused by Ab-mediated cross-linking of T cells and Fcgamma receptor (FcR)-bearing cells. With the goal of minimizing cytokine-induced toxicity, anti-CD3 have been engineered to lower Fc binding avidity. Preclinical murine studies have indicated that non-FcR-binding anti-CD3 can induce apoptosis of Ag-activated T cells. Since induction of T cell apoptosis may be an important mechanism of immunosuppression by anti-CD3, we tested whether Fc mutations affect the ability of anti-human CD3 to induce apoptosis of activated T cells. We compared wild-type murine anti-CD3, M291, and OKT3 and their humanized, FcR- and non-FcR-binding structural variants in quantitative assays of T cell apoptosis. Non-FcR-binding variants produced more sustainable phosphorylation of extracellular signal-regulated kinase-2, greater release of IFN-gamma, and more effectively caused activation-dependent T cell apoptosis. Non-FcR-binding variants dissociated more quickly from the T cell surface and caused less internalization of the TCR, which then remained available in greater abundance on the cell surface for signaling. Cross-linking of non-FcR-binding variants by antiglobulin enhanced TCR internalization and minimized induction of T cell apoptosis. We conclude that non-FcR-binding, humanized anti-CD3 have improved ability to induce apoptosis of activated T cells, presumably by allowing durable expression of the TCR and sustained signaling.

Adult↗