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M Gyger

Publications and source records attributed to M Gyger.

At least 37 records · Page 2Linked to original sources
PubMed1995

Immunodominant minor histocompatibility antigens expressed by mouse leukemic cells can serve as effective targets for T cell immunotherapy.

Numerous minor histocompatibility antigens (MiHAs) show tissue-specific expression and can induce vigorous T cell responses. They therefore represent attractive targets for leukemia immunotherapy mediated by adoptive transfer of T cells. The main objective of this work was to determine whether MiHAs expressed by normal hematopoietic cells were present on leukemic cells and whether they could trigger lysis by cytotoxic T lymphocytes (CTLs). CTL assays showed that mouse leukemic cells of both lymphoid and myeloid lineages were sensitive to CTLs targeted toward some but not all MiHAs. In four out of four strain combinations in which we primed CTLs against immunodominant MiHAs, effectors killed leukemic blasts, whereas no cytotoxicity was observed when CTLs were targeted toward four immunorecessive MiHAs. Testing of HPLC fractions obtained from normal and leukemic cells provided molecular evidence that leukemic blasts expressed only some of the MiHAs found on normal mouse hematopoietic cells. Decreased density of H-2 class I molecules at the surface of leukemic cells suggests that down-regulation of genes encoding either class I molecules or proteins involved in antigen processing played a role in the aberrant expression of MiHAs. In vivo resistance to the leukemic cells by various strains of mice correlated with in vitro CTL activity. These results show that leukemic cells express only some (immunodominant) MiHAs and suggest that this subset of MiHAs represent prime targets for adoptive immunotherapy.

Animals↗
PubMed1995

Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia.

PURPOSE: Allogeneic bone marrow transplantation (BMT) has been shown to provide effective therapy for chronic myelogenous leukemia (CML), but previous reports have also demonstrated the persistence of bcr-abl-positive cells for months to years after BMT in the majority of patients. To evaluate the biologic significance of persistent bcr-abl-positive cells, we examined the relationship between clinical parameters known to affect the risk of relapse and the ability to detect bcr-abl-positive cells post-BMT. PATIENTS AND METHODS: We analyzed 480 samples from 92 patients at two transplant centers for the presence of bcr-abl-positive cells by polymerase chain reaction (PCR). Two different BMT preparative regimens and protocols for prevention of graft-versus-host disease (GVHD) were used. One center used cyclophosphamide plus total-body irradiation (CY/TBI) and T-cell-depleted marrow; the second center used busulfan plus cyclophosphamide (Bu/CY) and untreated marrow with cyclosporine and methotrexate (Csp/MTX) as GVHD prophylaxis. RESULTS: We first determined the percent of patients at each center with > or = one PCR-positive (PCR+) result at defined intervals post-BMT. Between 0 and 6 months post-BMT, the majority of patients (80% to 83%) in both populations had PCR-detectable bcr-abl-positive cells. Between 6 and 24 months post-BMT, 80% to 88% of patients who received T-cell-depleted marrow remained PCR+, as compared with 26% to 30% of patients who received unmodified marrow. After 24 months post-BMT, the percentage of PCR+ patients was not significantly different in the two populations. This pattern of detection of bcr-abl-positive cells post-BMT followed the development of chronic GVHD in patients who received unmodified marrow. All patients were also divided into three groups based on post-BMT PCR results as follows: (1) persistent PCR+ (n = 29), (2) intermittent PCR-negative ([PCR-] n = 40), and (3) persistent PCR- (n = 23). These three groups were found to have a low, intermediate, and high probability of maintaining remission and disease-free survival, respectively (P = .0001). Intermittent or persistent PCR- results, which reflect levels of minimal residual disease < or = the limit of detection by PCR, were clearly associated with both acute (P = .004) and chronic (P = .000005) GVHD. Nevertheless, 44% of patients without GVHD also had intermittent or persistent PCR- assays. CONCLUSION: The persistence of PCR-detectable bcr-abl-positive cells early post-BMT in more than 80% of patients suggests that neither BMT preparative regimen effectively eradicates CML cells in most patients. Subsequently, acute and/or chronic GVHD are associated with a decreased ability to detect residual bcr-abl-positive cells, which suggests that immunologic mechanisms mediated by donor cells are important for inducing long-term remissions after BMT. The demonstration that 44% of patients without GVHD had either low or undetectable levels of residual leukemia suggests the presence of mechanisms capable of suppression or eradication of CML independent of GVHD.

Acute Disease↗
PubMed1993

Allogeneic bone marrow transplantation following busulfan-cyclophosphamide with or without etoposide conditioning regimen for patients with acute lymphoblastic leukaemia.

We have investigated the feasibility and efficacy of administering a radiation-free preparative regimen in the setting of allogeneic bone marrow transplantation (BMT) in 40 consecutive patients with acute lymphoblastic leukaemia (ALL). Busulfan (4 mg/kg/d x 4 d) and cyclophosphamide (50 mg/kg/d x 4 d) (BuCy4) were given in 29 patients and 11 received busulfan (4 mg/kg/d x 4 d), etoposide (60 mg/kg) and cyclophosphamide (60 mg/kg/d x 2 d) (BuCy+VP - 16). Median age was 22 years (range 1-50); 11 patients were children < or = 15 years of age. All children and 20 adults were at high risk of relapse pretransplant. Nine adults and one child died from transplant-related toxicity. 11 patients relapsed at a median of 11 months post-transplant (range 2-27). The 3-year Kaplan-Meier estimated probability of relapse was 42.1% and found to be significantly lower in patients with chronic GVHD (P = 0.03). 19 patients are leukaemia-free survivors with a median follow-up of 33 months (range 7-59). The Kaplan-Meier actuarial probability of disease-free survival at 3 years was 43% for all patients. 63.6% for children versus 30.2% for adults (P = 0.24) and 51.6% for patients transplanted in first remission versus 30.2% for those transplanted in subsequent remissions (P = 0.20).

Adolescent↗
PubMed1992

Cytogenic characterization of primary refractory anemia.

Refractory anemia (RA) is the only myelodysplastic syndrome (MDS) devoid of quantitative marrow diagnostic criteria. The diagnosis rests mainly on the subjective identification of qualitative abnormalities according to the French-American-British criteria (FAB) involving one or more bone marrow hematopoietic cell lineages. The occurrence of nonrandom chromosome abnormalities remains the hallmark of the disease and the only means of investigation which confirms the disease objectively. With the purpose in mind to further characterize RA among MDS, we have undertaken a prospective high resolution banding chromosome analyses of bone marrow cells in patients with primary refractory anemia (PRA) with the aim of defining a cytogenetic phenotype and of assessing the clinical relevance of clonal abnormalities at initial diagnosis. Of 39 patients consecutively referred for chromosome analyses with a diagnosis of RA according to the FAB criteria, 27 patients had PRA and fulfilled our criteria for adequate chromosome analyses. Median age was 68 years. Fourteen of 27 patients (52%) had clonal chromosomal abnormalities at diagnosis. None of the patients showed a complex karyotype; 9/14 (64%) had a mixture of normal and abnormal cells. Interstitial or terminal deletions, involving chromosomes 5, 6, 7, 9, 11, 12, and 20, were found in 11/14 (79%) of the patients. Comparison of survival between patients with and without abnormalities showed no difference. The presence of clonal abnormalities did not predict transformation to acute myeloblastic leukemia (AML) nor was it associated with poor survival. In this study, patients with PRA were found to have a predominant pseudodiploid karyotypic pattern characterized by interstitial and/or terminal deletions as opposed to derivatives, specific and non-specific balanced translocations, or other structural and numerical abnormalities. We were unable to reveal any prognostic significance to the presence of these clonal abnormalities at initial diagnosis.

Adult↗
PubMed1991

Vibrissa-related behavior in mice: transient effect of ablation of the barrel cortex.

Knowing that the mystacial vibrissae are an important part of the tactile sensory apparatus of rodents, we investigated the role of the barrel cortex - the endstation of the pathway between whiskerpad and cerebral cortex - in mouse behavior. We tested 15 female adult mice 2 and 10 weeks after both unilateral ablation of the barrel cortex and removal of the vibrissae on the same side in order to assess acute as well as transient effects of the cortical lesion. Two kinds of behavioral tests were performed on animals permanently provided with opaque lenses: one involved a passive stimulation of the vibrissae; the other was the 'gap-crossing' test which required the animal's active use of the vibrissae. Lesioned subjects did not show a deficit during passive stimulation of the vibrissae. On the contrary, there was a deficit during the gap-crossing test 2 weeks after the ablation of the barrel cortex. The deficit partly disappeared when the subjects were tested 10 weeks later. The results show that in mice, the barrel cortex is involved in the performance of complex behavioral tasks. The recovery of function could be due to changes in strategies to solve the gap-crossing test and/or to physical changes in neuronal circuitry. In either case, the results are relevant for the interpretation of cortical transplantation models using the whisker-to-barrel pathway.

Animals↗
PubMed1990

Studies of immunologic tolerance to host minor histocompatibility antigens following allogeneic bone marrow transplantation in mice.

We showed previously that transplantation of 10(7) unmanipulated C57BL/6 marrow cells to irradiated LP mice yields healthy (B6-LP) chimeras showing no signs of rejection or graft-versus-host disease (GVHD). The aim of this work was to gain more insight into the mechanism(s) responsible for tolerance to host minor histocompatibility antigens following allogeneic bone marrow transplantation (BMT). (B6-LP) chimeras showed very good immune reconstitution when studied in vitro for proliferative response to mitogens and alloantigens and generation of T cell cytotoxic activity. In co-culture experiments their spleen cells showed no natural suppressor activity. When used as cell donors, their capacity to initiate GVHD in four strains of mice presenting H-2 differences was normal when compared to C57BL/6 donors. However, they provoked no GVHD in the three strains of H-2 compatible mice studied. Re-irradiated (B6-LP) chimeras rapidly died of GVHD following injection of C57BL/6 marrow + spleen cells. (B6-LP.R111) chimera cells appeared tolerant to LP minor antigens presented in the context of H-2r or H-2b. No anamnestic anti-idiotypic suppressor response was noted when stable (B6-LP) chimeras were stimulated with naive C57BL/6 cells. These findings suggest that in BMT chimeras transplanted across minor histocompatibility barriers: (1) both host and donor-derived antigen-presenting cells can present host antigens to donor T cells whose numbers in the marrow inoculum will determine if GVHD or tolerance will ensue, (2) GVHD can be triggered by only a limited number of 'dominant' minor antigens, and (3) we found no evidence for the presence of natural suppressors, veto cells or anti-idiotypic suppressor T cells.

Animals↗
PubMed1989

Translocation (1;5)(q23;q33) in adult acute non-lymphocytic leukemia.

Chromosome banding studies carried out on bone marrow cells from a 57-year-old white caucasian male with an M1 acute non-lymphocytic leukemia (ANLL) revealed an unbalanced translocation involving chromosomes 1 and 5 [der(5)t(1;5)(q23;q33)] as part of complex abnormalities in 76% of the cells analyzed. This chromosomal abnormality is the first to be reported in an adult patient with acute non-lymphocytic leukemia. A review of previous reports on translocations involving the juxtaposition of the 1q23----qter DNA segment to other chromosomes suggests that this new translocation may be specifically involved with abnormal myeloid proliferation.

Bone Marrow Cells↗
PubMed1989

Chronic B-cell lymphocytosis.

Persistent elevation of lymphocyte counts is usually associated with a malignant monoclonal lymphoproliferative disease. Over the last 8 years, amongst patients investigated in our center for undetermined persistent lymphocytosis, a diagnosis of malignant lymphoproliferation was excluded in 6 cases as studies of surface membrane immunoglobulin light chains showed that they presented a polyclonal expansion of their B-lymphocyte pool. All patients were young-to-middle aged women presenting peculiar immunohematologic findings characterized by 1) persistent (2-7 yr) elevation of lymphocyte counts (4-14 x 10(9)/l), 2) presence of characteristic binucleated B cells on peripheral blood smears, 3) a normal bone marrow histology, 4) a polyclonal increase of serum IgM with low-to-normal IgG and IgA levels. Histologic examination of the spleen in 2 patients and lymph nodes in 1 showed a benign follicular lymphoid hyperplasia. The evolution was benign in every case. We suggest that chronic polyclonal B-cell lymphocytosis is a distinct clinicopathologic entity that should not be confused with malignant lymphoproliferative disorders.

Adult↗
PubMed1989

The mechanism of graft-host-tolerance in murine radiation chimeras transplanted across minor histocompatibility barriers.

A better understanding of the mechanism(s) involved in graft-host-tolerance following allogeneic bone marrow transplantation is needed to develop new strategies to prevent graft-versus-host disease (GVHD). Based on previous studies, mainly in MHC-mismatched donor-recipient pairs, three hypotheses have been proposed: clonal deletion, active suppression and lack of adequate antigen-presenting cells. Our goal was to identify the mechanism(s) by which tolerance is achieved and maintained in radiation chimeras transplanted across minor histocompatibility barriers. Healthy (B6----LP) chimeras were obtained following injection of 10(7) C57BL/6 marrow cells to irradiated (9.5 Gy) LP hosts and used experimentally 100 days after chimerization. The tolerance state of (B6----LP) chimeras could not be abrogated after i.v. transfer of 5 x 10(7) donor-type spleen cells alone or with repeated i.p. injection of host-type antigen-presenting cells. No GVHD was observed when 10(7) marrow cells plus 5 x 10(7) spleen cells from (B6----LP) chimeras were injected to irradiated LP recipients. Chimera spleen cells suppressed GVHD when adoptively transferred to LP recipients of a C57BL/6 graft. These results suggest that in this model the presence of suppressor cells is both necessary and sufficient to maintain graft-host-tolerance.

Animals↗
PubMed1988

Prognostic value of clonal chromosomal abnormalities in patients with primary myelodysplastic syndromes.

Chromosome analyses were carried out on bone marrow cells from 43 consecutive patients with primary myelodysplastic syndromes (MDS), classified according to the French-American-British (FAB) cooperative group criteria. The objective was to evaluate the prognostic value of clonal chromosomal abnormalities and of an excess of blasts for early death from acute nonlymphocytic leukemia (ANLL) and/or bone marrow failure (BMF). Patients were subdivided into two main groups: (1) refractory anemia without an excess of blasts (RAWEB), grouping patients with refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS), and (2) refractory anemia with an excess of blasts (RAEB), grouping patients with refractory anemia with an excess of blasts (RAEB) and refractory anemia with an excess of blasts in transformation (RAEBt). There were 29 patients with RAWEB and 14 with RAEB. The median time of observation was 26 months for RAWEB and 12 months for RAEB. Ten RAWEB patients (34%) and 11 RAEB patients (78%) had clonal chromosomal abnormalities. Among the ten RAWEB patients with clonal abnormalities, one (10%) died from ANLL, while of 19 RAWEB patients with a normal karyotype, two (10%) died from ANLL or BMF. The median survival for patients with RAWEB and an abnormal karyotype was not reached. In contrast, eight of the 11 RAEB patients with clonal chromosomal abnormalities (74%) died from ANLL or BMF. The median survival in this sub-group was 7 months. By using a Cox proportional hazard regression analysis, it was determined that a karyotype abnormality was not a significant predictory of survival once the contribution of the RAWEB/RAEB variable was taken into account. Being in the RAEB group was associated with a relative risk of 10.6 of dying from ANLL or BMF (beta = 2.36, standard error (SE) = 0.68, P = .0001). We conclude that classifying patients according to an excess of blasts will lead to a better prediction of survival than determining karyotype abnormality.

Adult↗
PubMed1988

Alarm signals in birds: the role of testosterone.

In the laboratory and under semi-naturalistic conditions, male domestic fowl (Gallus gallus) produce more alarm calls in response to predatory birds flying overhead than females. This study tests the hypothesis that testosterone is a factor in the control of aerial alarm call production. Birds were castrated early in life and tested as adults in the laboratory. Aerial predators were simulated by cardboard silhouettes drawn overhead. Blood samples were taken at intervals and plasma testosterone levels were measured by radioimmunoassay. Each subject was tested in four conditions: with an empty Silastic implant, with a testosterone-filled implant, with an additional testosterone implant, and after removal of the implants. Results show that the presence of testosterone increases the production of aerial alarm calls, and that removal of the hormone supply results in a drop in calling rate. As a control a second vocal system, food calling, was considered. In contrast with alarm calling, there was no correlation between testosterone levels and variation in food-call production. We conclude that testosterone plays a specific role in activation of the production by cockerels of vocalizations that signal the presence of aerial predators.

Animals↗
PubMed1988

Audience effects on alarm calling in chickens (Gallus gallus).

The male domestic chicken (Gallus gallus) has been found to modulate the production of vocal signals in response to the presence or absence of a suitable audience. We investigated effects on alarm calling by presenting overhead predator models to cockerels in the presence of a variety of social companions. The production of aerial predator calls in response to hawk silhouettes varied with the presence or absence of a member of the same species. The kinds of audience investigated included the mate, unfamiliar females, other females and males with which subjects had had prior visual and auditory contact, and broody hens with and without young. Domestic chicks, unrelated to the subjects, were almost as effective an audience as conspecific adults. A member of another species, however, failed to potentiate alarm-call production. The subjects gave more alarm calls when they were in the presence of either a male or a female audience than when they were alone. By manipulating the visibility of overhead predator models to the subjects and to the audience, we showed that the subjects were not cued by alarm and escape behaviors of the audience. Comparisons with food calling indicate that, in deciding whether to emit a signal in response to the appropriate referent (e.g., food or predators), chickens respond to subtle differences in the nature of the audience with behaviors that vary from one communicative context to another.

Animals↗
PubMed1988

Bone marrow transplantation for myelodysplastic syndromes.

Eight patients with myelodysplastic syndromes (MDS) were treated with bone marrow transplantation (BMT). Median age was 34.5 years and ranged between 3 and 45. FAB diagnosis was refractory anaemia (RA) in three, RA with excess of blasts (RAEB) in four and RAEB in transformation (RAEB-t) in one case. Four patients were prepared with cyclophosphamide and total body irradiation whilst the other four received busulphan and cyclophosphamide. Engraftment was documented in seven of eight patients. Two patients died from complications related to the procedure. One had early veno-occlusive disease of the liver whilst the other died 46 months after BMT from pulmonary fibrosis. One patient died from recurrent disease 11 months after BMT. Five patients are alive and in complete remission 9-35 months post-transplantation. Four of these patients have a Karnofsky score greater than or equal to 90%. These results suggest that BMT can induce prolonged disease-free survival in patients under 50 years of age. If a compatible donor is available, marrow transplantation should be seriously considered in the treatment of MDS.

Adult↗