Surfactant protein A is a required mediator of keratinocyte growth factor after experimental marrow transplantation

2003 ◽  
Vol 285 (3) ◽  
pp. L602-L610 ◽  
Author(s):  
Imad Y. Haddad ◽  
Carlos Milla ◽  
Shuxia Yang ◽  
Angela Panoskaltsis-Mortari ◽  
Samuel Hawgood ◽  
...  

We reported an association between the ability of recombinant human keratinocyte growth factor (rHuKGF) to upregulate the expression of surfactant protein A (SP-A) and to downregulate pulmonary inflammation that occurs after allogeneic bone marrow transplantation (BMT). To establish a causal relationship, rHuKGF (5 mg/kg) was administered subcutaneously for three consecutive days before irradiation to SP-A-sufficient and -deficient [SP-A(+/+) and SP-A(-/-), respectively] mice given inflammation-inducing allogeneic spleen T cells at the time of BMT. In contrast with SP-A(+/+) mice, rHuKGF failed to suppress the high levels of TNF-α, IFN-γ, and nitric oxide contained in bronchoalveolar lavage fluids collected on day 7 after BMT from SP-A(-/-) mice. Early post-BMT weight loss was attenuated by rHuKGF in both SP-A(+/+) and SP-A(-/-) recipients. In the absence of supportive respiratory care, however, SP-A deficiency eventually abolished the ability of rHuKGF to prevent weight loss and to improve survival monitored for 1 mo after allogeneic BMT. In further experiments, the addition of cyclophosphamide (which is known to cause severe injury to the alveolar epithelium in donor T cell-recipient mice) to the conditioning regimen prevented rHuKGF-induced upregulation of SP-A and suppression of lung inflammation in both SP-A(+/+) and SP-A(-/-) mice. We conclude that endogenous baseline SP-A levels and optimal upregulation of SP-A are required for the anti-inflammatory protective effects of KGF after allogeneic transplantation.

2007 ◽  
Vol 62 (3) ◽  
pp. 277-282 ◽  
Author(s):  
Robert J Digeronimo ◽  
Shamimunisa B Mustafa ◽  
Rita M Ryan ◽  
Zohara Z Sternberg ◽  
Daniel J Ashton ◽  
...  

1991 ◽  
Vol 9 (7) ◽  
pp. 1224-1232 ◽  
Author(s):  
T J Nevill ◽  
M J Barnett ◽  
H G Klingemann ◽  
D E Reece ◽  
J D Shepherd ◽  
...  

The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac, bladder, renal, pulmonary, hepatic, CNS, stomatic, and gastrointestinal) according to a recently developed RRT scale. A set of patient, disease, and treatment parameters (age, sex, diagnosis, Eastern Cooperative Oncology Group [ECOG] score, preconditioning liver function tests [LFT], prior chemotherapy exposure, disease status, graft-versus-host disease [GVHD] prophylaxis, antimicrobial agent use, hematologic recovery, and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%, respectively) but were rarely serious (9% and 1% grades II to IV, respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven), pulmonary (two), bladder (two), and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis, only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%, with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.


Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 825-831 ◽  
Author(s):  
Oleg I. Krijanovski ◽  
Geoffrey R. Hill ◽  
Kenneth R. Cooke ◽  
Takanori Teshima ◽  
James M. Crawford ◽  
...  

Abstract The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF) levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42%v 4%, P < .001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD.


1995 ◽  
Vol 13 (12) ◽  
pp. 2973-2979 ◽  
Author(s):  
M R O'Donnell ◽  
G D Long ◽  
P M Parker ◽  
J Niland ◽  
A Nademanee ◽  
...  

PURPOSE A non-radiation-containing regimen of busulfan and cyclophosphamide (BU/CY) was evaluated for toxicity, relapse, and long-term survival in patients who received allogeneic bone marrow transplantation (BMT) for myelodysplasia (MDS). PATIENTS AND METHODS Thirty-eight patients with MDS, including eight with therapy-related MDS, were prepared for BMT using BU/CY. RESULTS Fourteen patients remain in first remission 18 to 60 months posttransplant. Five patients relapsed after BMT, and four of these patients died. Eight additional patients died of acute or chronic graft-versus-host disease (GVHD), and 11 died of regimen-related toxicity, primarily systemic mycoses. Overall survival rate at 2 years was 45% (95% confidence interval [CI], 0.30 to 0.61), with a 24% probability of relapse (95% CI, 0.10 to 0.49). Regimen-related toxicity was manifested primarily as hepatic dysfunction in 72% of patients, with 16% developing overt venoocclusive disease (VOD). CONCLUSION Non-radiation-containing preparative regimens offer long-term survival in allogeneic BMT for MDS that is comparable to that of radiation-containing regimens, and are useful in patients with therapy-related MDS. Monitoring BU levels may reduce regimen-related mortality and improve survival.


2002 ◽  
Vol 27 (3) ◽  
pp. 297-305 ◽  
Author(s):  
Shuxia Yang ◽  
Carlos Milla ◽  
Angela Panoskaltsis-Mortari ◽  
Samuel Hawgood ◽  
Bruce R. Blazar ◽  
...  

Author(s):  
Jeffrey A. Whitsett ◽  
Ailsa Budden ◽  
William M. Hull ◽  
Jean C. Clark ◽  
Michael A. O'Reilly

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1583-1586 ◽  
Author(s):  
JF Sheridan ◽  
PJ Tutschka ◽  
DD Sedmak ◽  
EA Copelan

Serum immunoglobulin (Ig) G subclass levels were measured in a radial immunodiffusion assay in 25 leukemic patients before and after allogenic bone marrow transplantation. All patients received a conditioning regimen of busulfan and cyclophosphamide followed by infusion of marrow from an HLA-identical sibling. Intravenous infusions of a commercial Ig preparation were administered every 2 weeks until day 120 posttransplant. Nine patients developed pneumococcal infections at 6 months or greater posttransplant. Infection was associated with low levels or the absence of detectable serum IgG2 and IgG4. At the time of infection, 4 of 7 patients evaluated had undetectable IgG2, while 5 of 7 had undetectable levels of IgG4. After infection, none of the 8 patients evaluated had detectable levels of IgG2, and only 2 of 8 had detectable levels of IgG4. In contrast, all 16 patients without pneumococcal infection had IgG2 levels of 102 mg/dL or greater, and IgG4 levels of 20 mg/dL or greater. It appears that IgG2 and IgG4 subclass deficiencies after allogenic bone marrow transplantation contribute to susceptibility to pneumococcal infection. After pneumococcal infection, IgG2 and IgG4 levels remain low for a prolonged period and patients remain susceptible to infection by encapsulated organisms.


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