Biomedical subjects
Publications and source records attributed to M Cottler-Fox.
The follicular dendritic cells (FDCs) of the germinal center are known to absorb antigens in the form of immune complexes and to express them on the cell surface for long periods of time. Here, Cecil Fox and Michele Cottler-Fox propose that, as a result of FDC binding of immune-complexed viruses, lymphoid organs are the major reservoirs of HIV, and that FDCs play a key role in infection of CD4+ T cells.
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PURPOSE: High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS: Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS: Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION: High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.
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Multiple benefits of intravenous immunoglobulin (IVIG) therapy after marrow transplantation have been reported, including decreased incidence of acute graft-versus-host disease (GVHD), infection, sepsis, cytomegalovirus (CMV) pneumonitis and platelet use. To test the hypothesis that the observed beneficial effects of IVIG are related to the serum IgG levels achieved, we followed IgG levels (pre-infusion, 1 h and 24 h post-infusion) in 45 consecutive marrow transplant recipients. IVIG 500 mg/kg was given weekly for six doses starting day -8 pre-transplant, then every other week for a total of 11 doses. Forty-one patients (22 allogeneic, 17 autologous, two syngeneic) were evaluable. Patients with acute GVHD had significantly lower serum IgG trough levels (less than 1200 mg/dl) noted at day +20 post-transplant and afterwards than patients without GVHD (greater than or equal to 1200 mg/dl). Pharmacokinetic modeling of the data indicates that IgG half-life between day -8 and day +6 may predict which recipients are at increased risk of acute GVHD. Allogeneic recipients in the group with trough levels less than 1200 mg/dl required more platelet transfusions. Although there was no significant difference in fungal infection rates or bacteremia, sepsis was noted in only two recipients (one allogeneic, one autologous), both with serum IgG trough levels less than 1200 mg/dl. In addition, three allogeneic recipients had cytomegalovirus pneumonitis, all in the group with lower IgG trough levels. Thus, while serum IgG trough levels less than 1200 mg/dl appear to be strongly associated with acute GVHD, low levels may also be associated with increased platelet utilization, with cytomegalovirus pneumonitis, and sepsis, but not with the overall incidence of infection.
Intensive chemoradiotherapy conditioning regimens and acute graft-versus-host disease (GVHD) are both associated with significant morbidity and mortality after bone marrow transplantation. In this study, we investigated whether the conditioning regimen affected the development of acute GVHD. Thirty-four patients, four with severe aplastic anemia and 30 with a lymphohemopoietic malignancy, were prepared for transplantation either with cyclophosphamide (CY) alone, with CY combined with total body irradiation (TBI) or CY combined with etoposide and either TBI or busulfan. GVHD prophylaxis included methotrexate (MTX 10 mg/m2) given on days 1, 3 and 6, and daily cyclosporine (CSP) on days--1 through 180. The overall incidence of acute GVHD was 36% (15% for HLA identical, 87% for HLA non-identical recipients). However, when assessed by the severity of conditioning regimen-related toxicity, the incidence of GVHD grades II-IV (HLA identical; HLA non-identical) was 0% (0%; 0%), 37% (20%; 67%) and 50% (22%; 100%) for patients with mild, moderate and severe toxicity, respectively. Compliance with GVHD prophylaxis declined with increasing intensity and toxicity of the conditioning regimen. These data suggest that a regimen of three doses of MTX and daily CSP is as effective as four doses of MTX/CSP for GVHD prophylaxis in patients given HLA identical marrow grafts. However, GVHD regimen compliance and efficacy of GVHD prevention are inversely related to the intensity of the conditioning regimen.
A case of transfusion-induced graft-versus-host disease (GVHD) occurring in a 31-year-old female with Hodgkin's disease in complete remission is reported. Clinical features are similar to 19 other reported cases of transfusion-induced GVHD associated with malignant lymphoma. The lack of relationship with underlying histology or disease stage and the nearly uniformly fatal outcome underscores the importance of prophylactic irradiation of blood products given to patients with malignant lymphoma undergoing therapy.
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A 35-year-old caucasian man developed mild and transient signs of chronic graft-versus-host disease (GVHD) 5 months after bone marrow transplantation. At 16 months he presented with painful cramps in hands, feet, and truncal muscles. Electrophysiological studies revealed generalized sensory neuropathy. There was occasional fasciculation and high frequency motor units during involuntary muscle contractions, and agonist/antagonist cocontractions of peripheral muscle groups (non-continuous). A sural nerve biopsy showed Schwann cells and macrophages with myelin debris, and Schwann cell stacks with collagen pockets. The patient's symptoms responded to treatment with glucocorticoids and azathioprine. We propose that this patient's incapacitating polyneuropathy was a major manifestation of chronic GVHD, suggesting that the peripheral and possibly central nervous systems can be targets of chronic GVHD.
A purified or enriched population of human marrow hemopoietic precursor cells may be produced by using a monoclonal antibody to specifically bind to the desired cell population (positive selection), or by removing undesired cell populations contaminating the mixture (negative selection). We describe a simple negative selection technique using commercially available monoclonal antibodies and immunomagnetic beads to produce a mononuclear marrow cell fraction which comprises no more than 2% of the initial cell population yet contains all the BFU-E and CFU-GM present originally. This procedure is an efficient method for producing hemopoietic precursor cells appropriate for studying cell-substrate adhesions, homing mechanisms, and response to growth factors without interference by contaminating accessory cells.
We describe a method for in vitro isolation of mononuclear cells from peripheral blood or bone marrow using a Fenwal CS3000 Apheresis device without employing density gradients or sedimenting agents. The automatic processing program requires minimal operator intervention and no subjective operator decisions. A mean of 67% of starting mononuclear cells were recovered in a 100 ml product having 95% mononuclear cells and less than 1% of the original red blood cells. The average processing time was 35 minutes.
Urine cytology was studied prospectively for the presence of human polyomavirus (HPV) in 17 consecutive patients undergoing marrow transplantation and correlated with hematuria and hemorrhagic cystitis. Of the 15 evaluable patients, nine had cytologic findings consistent with HPV infection during the first month after transplantation. Of these nine patients, two had gross and seven had microscopic hematuria, all without symptoms of cystitis. Hematuria resolved within 30 days of onset, although three patients had persistent cytologic evidence of HPV until 100 days after transplantation. During the follow-up ranging from 8 to 14 months, none of the patients developed hemorrhagic cystitis. Our data do not support the relationship between HPV and prolonged or severe hemorrhagic cystitis previously suggested by others, nor did we see any late onset hemorrhagic cystitis.