Syndrome of Inappropriate Anti-Diuretic Hormone Secretion Secondary to Strongyloides stercoralis Infection in an Allogeneic Stem Cell Transplant Patient: A Case Report and Literature Review.

Syndrome of inappropriate anti-diuretic hormone (SIADH) has been reported to be associated with systemic Strongyloides stercoralis. Here, we report a case of a stem cell transplant (SCT) recipient who developed severe SIADH secondary to systemic S Stercoralis. The SIADH resolved quickly after treating the systemic S Stercoralis with ivermectin. A systematic review of the literature was performed by PubMed, Scopus, and Cochrane database search. Only eight cases of S Stercoralis in allogeneic SCT recipients have been previously reported. To our knowledge, ours is the first reported case of SIADH secondary to S Stercoralis infection in an allogeneic SCT recipient. Prior to transplantation, even if asymptomatic, patients from endemic regions should be screened with strongyloides immunoglobulin (Ig)G serology. Pretransplantation eosinophilia should be evaluated by screening multiple stool samples for ova and parasites. Transplant candidates with positive serology or stool tests can be treated pretransplantation to eradicate infection. Patients at risk for S Stercoralis who develop nonspecific gastrointestinal complaints, rash, pulmonary infiltrates, or gram-negative bacteremia or meningitis may have S Stercoralis hyperinfection syndrome. Our case indicates that the development of SIADH may be an additional clue to this diagnosis. Appropriate diagnostic studies, including repeat stool and other body fluid sampling, should be expedited and ivermectin therapy initiated rapidly to prevent significant morbidity and mortality.

PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies.

PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0 mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.

Leukemia burden delays lymphocyte and platelet recovery after allo-SCT for AML.

Lymphocyte and platelet recovery may influence outcomes of allo-SCT for treatment of AML. It is not clear, however, if this impact is independent of patient and transplant characteristics. To investigate this question, we evaluated the influence of pre- or post transplant factors on day +30 absolute lymphocyte count (ALC) and the speed of platelet engraftment. We studied 106 AML patients treated with fludarabine and melphalan reduced-intensity conditioning and allo-SCT. Twenty nine percent of patients were in CR at the initiation of the conditioning, 39% had active disease with circulating blasts and 32% had active disease without circulating blasts. The graft source was peripheral blood from a matched sibling donor in 55% and BM from a matched unrelated donor in 45%. Our data showed that the presence of circulating blasts before transplantation is significantly correlated with low post-SCT day +30 ALC and slow platelet engraftment. This finding suggests that the impact of early ALC and platelet recovery on transplant outcome may not be independent of disease status at transplantation.

Comparison between real-time intra-operative ultrasound-based dosimetry and CT-based dosimetry for prostate brachytherapy using cesium-131.

The purpose of this study was to evaluate the correlation between real-time intra-operative ultrasound-based dosimetry (USD) and day 0 post-implant CT dosimetry (CTD) (131)Cs permanent prostate brachytherapy. Fifty-two consecutive patients who underwent prostate brachytherapy with (131)Cs were evaluated. Real time operating room planning was performed using VariSeed 7.1 software. Post-needle placement prostate volume was used for real-time planning. Targets for dosimetry were D(90) >110%, V(100) >90%, V(150) <50%, and V(200) <20%. The CT scan for post-operative dosimetry was obtained on day 0. The mean values for USD, CTD, and the linear correlation, respectively, were, for D(90): 114.0%, 105.61%, and 0.15; for V(100): 95.1%, 91.6%, and 0.22; for V(150): 51.5%, 46.4%, and 0.40; and for V(200): 15.8%, 17.9%, and 0.42. The differences between the mean values for USD and CTD for D(90) (p<0.01), V(100) (p<0.01), and V(150) (p<0.05) were statistically significant. For D(90), 30.8% of patients had a >15% difference between USD and CTD and 51.9% of patients had a >10% difference between these values. In contrast, the USD and CTD for V(100) were within 5% in 55.8% of patients and within 10% in 86.5% of patients. This study demonstrates a correlation between the mean intra-operative USD and post-implant day 0 CTD values only for V(200). Significant variation in D(90), V(150), and V(200) values existed for individual patients between USD and CTD. These results suggest that real-time intra-operative USD does not serve as a surrogate for post-operative CTD, and that post-operative CTD is still necessary.

Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial.

The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133+ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained <2 x 10(7) total nucleated cells (TNCs) per kilogram pre-expansion. All donor-recipient pairs were mismatched for one or two HLA loci. Nine patients were beyond first remission; median age and weight were 21 years and 68.5 kg. The average TNCs fold expansion was 219 (range, 2-620). Mean increase of CD34+ cell count was 6 (over the CD34+ cell content in the entire unit). Despite the low TNCs per kilogram infused (median=1.8 x 10(7)/kg), nine patients engrafted. Median time to neutrophil and platelet engraftment was 30 (range, 16-46) and 48 (range, 35-105) days. There were no cases of grades 3-4 acute graft-versus-host disease (GVHD) and 100-day survival was 90%. This strategy is feasible.

Inhaled corticosteroids stabilize constrictive bronchiolitis after hematopoietic stem cell transplantation.

Post transplantation constrictive bronchiolitis (PTCB) is the most common pulmonary complication among long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). It is a late manifestation of GVHD. Its treatment with high-dose systemic corticosteroids and other immunosuppressive regimens is associated with multiple side effects. Topical corticosteroids are used for the treatment of other manifestations of GVHD to minimize these side effects. We conducted a retrospective analysis of a series of adult patients to evaluate the efficacy of high-dose inhaled corticosteroids in the treatment of PTCB. Seventeen patients with new-onset airflow obstruction were diagnosed with PTCB. Their forced expiratory volume in 1 s (FEV1) declined from a median of 84% (range, 56-119) before HSCT to 53% (26-82) after HSCT. All patients received inhaled fluticasone propionate 500-940 microg two times daily. Symptoms of airway obstruction improved and FEV1 stabilized 3-6 months after treatment. We conclude that high-dose inhaled corticosteroids may be effective in the treatment of PTCB and propose a plausible mechanism of its action. A prospective evaluation of its efficacy is warranted.

Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies.

We analyzed the clinical factors associated with late cytomegalovirus (CMV) reactivation in a group of 269 consecutive recipients of allogeneic stem cell transplant (SCT) for hematological malignancies. Eighty-four subjects (31%) experienced late CMV reactivation, including 64 with prior early reactivation and 20 with isolated late reactivation. Multivariate analyses were conducted in patients with early CMV reactivation to identify factors associated with late recurrence. Important risk factors included lymphoid diagnosis, occurrence of graft-versus-host disease (GVHD), greater number of episodes of early reactivation, persistent day 100 lymphopenia and the use of a CMV-seronegative donor graft. We combined these risk factors in a predictive model to identify those at relatively low, intermediate and high risk. The low-risk group (15% cumulative incidence, CI) encompassed patients without early CMV reactivation, and subjects transplanted for a myeloid malignancy from a matched-related (MR) donor without subsequent acute GVHD. The high-risk patients (73% CI) met all of the following criteria: (1) received an MR graft but developed GVHD, or received a non-MR graft irrespective of GVHD; (2) had more than two episodes of early reactivation; and (3) received a CMV-seronegative graft and/or remained persistently lymphopenic at day 100 after SCT. The remaining patients had an intermediate incidence of 32%.

AML-loaded DC generate Th1-type cellular immune responses in vitro.

BACKGROUND: The generation of AML-specific T-lymphocyte responses by leukemia-derived DC has been documented by multiple investigators and is being pursued clinically. An obstacle to widespread use of this strategy is that it has not been possible to generate leukemic DC from all patients, and an alternative approach is needed if the majority of leukemia patients are to receive therapeutic vaccination in conjunction with other treatment protocols. METHODS: In the present study, we generated DC from CD14-selected monocytes isolated from healthy donor PBPC and loaded them with a total cell lysate from AML patient blasts. RESULTS: Immature in vitro-derived DC exhibited robust phagocytic activity, and mature DC demonstrated high expression of CD80, CD83, CD86 and the chemokine receptor CCR7, important for DC migration to local lymph nodes. Mature, Ag-loaded DC were used as APC for leukemia-specific cytotoxic T-lymphocyte (CTL) induction and demonstrated cytotoxic activity against leukemic targets. CTL lysis was Ag-specific, with killing of both allogeneic leukemic blasts and autologous DC loaded with allogeneic AML lysate. HLA-matched controls were not lysed in our system. DISCUSSION: These data support further research into the use of this strategy as an alternative approach to leukemia-derived DC vaccination.

Ex vivo expanded umbilical cord blood T cells maintain naive phenotype and TCR diversity.

BACKGROUND: Umbilical cord blood (CB) is a promising source of hematopoietic stem cells for allogeneic transplantation. However, delayed engraftment and impaired immune reconstitution remain major limitations. Enrichment of donor grafts with CB T cells expanded ex vivo might facilitate improved T-cell immune reconstitution post-transplant. We hypothesized that CB T cells could be expanded using paramagnetic microbeads covalently linked to anti-CD3 and anti-CD28 Ab. METHODS: CB units were divided into three fractions: (1) cells cultured without beads, (2) cells cultured with beads and (3) cells cultured with beads following CD3+ magnetic enrichment. All fractions were cultured for 14 days in the presence of IL-2 (200 IU/mL). RESULTS: A mean 100-fold expansion (range 49-154) of total nucleated cells was observed in the CD3+ magnetically enriched fraction. Following expansion, CB T cells retained a naive and/or central memory phenotype and contained a polyclonal TCR diversity demonstrated by spectratyping. DISCUSSION: Our data provide evidence that naive and diverse CB T cells may be expanded ex vivo and warrant additional studies in the setting of human CB transplantation.

Thymic function and allogeneic T-cell responses in stem-cell transplantation.

The thymus is the primary site of T-cell production early in life, and has now been shown to continue to function in both healthy and immunocompromised individuals late into life. Positive and negative selection occurring in the thymus are two of the most important processes that govern the development and specificity of peripheral T cells, including their restriction to self HLA and their ability to respond in an alloreactive manner. In the chimeric state that follows successful allogeneic stem-cell transplants, the specificity of alloreactive cells may be governed by either host- or recipient-derived cellular elements, as well as maturing lymphoid cells, which are, in turn, derived from donor stem cells or host cells surviving transplant conditioning. The ability to measure recent thymic emigrants via the detection of T-cell receptor excision circles has facilitated studies of thymic function in immunodeficient individuals, including HIV-1 infected subjects and recipients of autologous or allogeneic stem-cell transplant (SCT). These studies have now demonstrated that thymic function is likely to play a beneficial role in immune reconstitution in these settings, but have yet to clearly demonstrate what clinical variables are the most important determinants of thymic persistence. It is also not yet clear how much the degree of thymic function following allogeneic SCT influences the alloreactive T-cell repertoire, although studies in animal models and early clinical studies suggest that GvHD results in thymic injury and dysfunction. Future studies will further clarify how thymic function shapes the repertoire of T cells that mediate alloreactivity, as well as protective pathogen-specific immune responses, following SCT. Finally, these studies will also demonstrate whether endogenous mediators of thymic function could be selectively applied to regulate post-SCT thymic function and alloreactivity.

Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis.

Clinical histories are reported for 2 patients treated with highly active antiretroviral therapy (HAART) who experienced multiple relapses of cytomegalovirus (CMV) retinitis, despite suppression of human immunodeficiency virus type 1 (HIV-1) viremia and improvement in CD4+ T cell counts (to >400 cells/microL). CMV-specific CD4+ T cell immune reconstitution was measured directly, using cytokine flow cytometry, which revealed persistent deficits in CMV-specific CD4+ T cell responses in both patients. CMV-specific T cells constituted 0.14% and 0.05% of the total CD4+ T cell count in these patients, which is significantly lower than the percentages for 34 control subjects (0.6%-46%; CD4+ T cell count range, 7-1039 cells/microL; P=.019). Deficits in pathogen-specific immune responses may persist in some individuals, despite suppression of HIV-1 replication and substantial increases in circulating CD4+ T cells after HAART, and such deficits may be associated with significant morbidity from opportunistic infections.

Direct measurement of CD4+ and CD8+ T-cell responses to CMV in HIV-1-infected subjects.

Data from murine models of chronic viral infection suggest that CD4+ T-cell responses to viral pathogens are important in sustaining the number and/or function of CD8+ cytotoxic T-cell (CTL) effectors. In this study, we used cytokine flow cytometry (CFC), staining with HLA-A*0201-peptide tetramers, and peptide stimulation with epitopic peptides to study functional CD4+ and CD8+ T-cell responses to cytomegalovirus (CMV) in human subjects coinfected with CMV and the human immunodeficiency virus, type 1 (HIV-1). We show that strong CD4+ and CD8+ T-cell responses to CMV antigens are sustained over time in HIV-1-infected individuals. Those who maintain a strong CD4+ T-cell response to CMV are also likely to maintain higher frequencies of CD8+ T cells capable of binding to HLA-A*0201-CMV pp65 (A2-pp65) tetramers as well as responses to pp65 peptide stimulation with effector cytokine production. These data support the hypothesis that declines in frequencies of CD4+ T-cell responses to CMV are associated with an inability to sustain high levels of CMV-specific CD8+ T-cell responses in HIV-1-infected subjects. These declines may precede the onset of CMV-associated end organ disease.

Direct evidence for thymic function in adult humans.

The understanding of human thymic function and evaluation of its contribution to T cell homeostasis are matters of great importance. Here we report the development of a novel assay to quantitate the frequency and diversity of recent thymic emigrants (RTEs) in the peripheral blood of humans. Such cells were defined by the presence of T cell receptor (TCR) rearrangement deletion circles (DCs), episomal byproducts of TCR-beta V(D)J rearrangement. DCs were detected in T cells in the thymus, cord blood, and adult peripheral blood. In the peripheral blood of adults aged 22 to 76 years, their frequency was highest in the CD4(+)CD45RA(+) CD62L(+) subpopulation of naive T cells. TCR DCs were also observed in other subpopulations of peripheral blood T cells, including those with the CD4(+)CD45RO(-)CD62L(+) and CD4(+)CD45RO(+)CD62L(+) phenotypes. RTEs were observed to have more than one Vbeta rearrangement, suggesting that replenishment of the repertoire in the adult is at least oligoclonal. These results demonstrate that the normal adult thymus continues to contribute, even in older individuals, a diverse set of new T cells to the peripheral circulation.

Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1.

Recent studies of subjects infected with human immunodeficiency virus (HIV-1) have produced conflicting results about the extent of reconstitution possible in the CD4+ lymphocyte repertoire after highly active antiretroviral therapy (HAART). The effect of HAART on the incidence of opportunistic infections will probably depend on reconstitution of antigen-specific CD4+ lymphocyte responses to important pathogens, including cytomegalovirus (CMV), the leading cause of blindness in AIDS. Several studies have demonstrated an important role for CD4+ lymphocytes in controlling CMV replication in vitro and in clinical studies. It is now possible to quantitate antigen-specific CD4+ lymphocyte responses by flow cytometry. Using this method, we studied CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 with and without a history of active CMV-associated end organ disease (EOD), and in those with quiescent CMV EOD after ganciclovir therapy and HAART. The presence of active CMV-associated EOD strongly correlated with loss of CMV-specific lymphocyte responses (P = 0.0004). In contrast, patients with no history of CMV-associated EOD and most patients with quiescent EOD after HAART demonstrated strong CMV-specific CD4+ lymphocyte responses. These data indicate that the loss of CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 who have active CMV EOD may be restored after ganciclovir therapy and HAART, which provides evidence for functional immune reconstitution to an important pathogen.

Superantigen-mediated deletion of specific T cell receptor V beta subsets in the SCID-hu Thy/Liv mouse is induced by staphylococcal enterotoxin B, but not HIV-1.

Infection by HIV-1 has been associated with perturbations in the TCR V beta repertoire, suggesting the involvement of a superantigen. Among the hallmarks of superantigens is the capacity to delete T cells bearing specific TCR V beta families in the developing thymus. To verify the presence of a superantigen in HIV-1, we analyzed the SCID-hu Thy/Liv TCR V beta repertoire within CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocytes subsets by flow cytometry using a panel of Abs recognizing about 60% of the TCR repertoire following injection of SEB or infection by two different HIV-1 isolates. Seven days following SEB injection, thymocyte subsets bearing TCR V beta 3, V beta 12, V beta 17, and V beta 20, but not V beta 5 or V beta 8 , were deleted relative to mock-injected mice. In contrast, no changes were observed in the TCR V beta repertoire in CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocyte subsets after infection with HIV-1. The T cell depletion caused by HIV-1 infection is most likely not mediated by an HIV-encoded superantigen.

The natural history and molecular heterogeneity of HIV-associated primary malignant lymphomatous effusions.

Primary malignant lymphomatous effusions arising in individuals infected with the human immunodeficiency virus, type 1 (HIV-1) represent a rare subset of HIV-associated lymphomas. Previous studies have demonstrated that the malignant cells are monoclonal (as defined by rearrangement of the immunoglobulin gene), express cell surface CD38, and are infected with Epstein-Barr virus (EBV) and human herpes virus, type 8 (HHV-8). Despite these detailed molecular and immunophenotypic studies, clinical information on this disease entity is scant, prompting us to review the clinical features of eight cases seen at our institutions. All eight patients had total peripheral CD4+ lymphocytes < 200/microliter and presented with complaints related to body cavity distension. Routine laboratory values were nondiagnostic and yielded no prognostic information. Only two patients could tolerate and thus received chemotherapy with no obvious impact on their clinical course. The mean overall survival after diagnosis was 60 days (range 6-166 days). Four patients were examined at autopsy. The primary malignant lymphomatous effusion either was the immediate cause of death or contributed significantly to the death of only two. All four patients examined post mortem, however, had lymphomatous infiltration of serosal surfaces adjacent to the site of the primary malignant effusion. Molecular and immunologic studies performed on the malignant cells and effusion fluids revealed universal expression of cell surface CD38 and the presence of HHV-8 gene sequences, but in contrast with previous studies, only four had rearranged immunoglobulin genes or EBV present: IL-6 and IL-10 levels in the malignant effusion fluids were markedly elevated. In summary, this rare subset of HIV-associated lymphomas in our eight patients arose late in the course of HIV-associated disease, had a rapid clinical course, and was molecularly heterogeneous. A pathogenetic role for HHV-8 alone in this disease process is strengthened by our observation of four cases lacking EBV but containing HHV-8.

Interleukin-8 inhibits non-small cell lung cancer proliferation: a possible role for regulation of tumor growth by autocrine and paracrine pathways.

Interleukin-8 (IL-8) is an 8 kD chemokine and angiogenic factor produced by alveolar macrophages, endothelial cells, monocytes, fibroblasts, T lymphocytes, and epithelial cells in response to a variety of stimuli, including LPS, TNF-alpha, IL-1, IL-7, and hypoxia. Pulmonary tumors produce a variety of growth factors and cytokines that may act in both autocrine and paracrine fashion. A549, a well-characterized human lung adenocarcinoma line, was cloned for different levels of IL-8 production by limiting dilution. Clone 3B4 produced 361 +/- 73 pg/ml, and clone 2B2 produced 7818 +/- 614 pg/ml of IL-8 (p = 0.003). Clone 3B4 proliferated at 1.7 times the rate of 2B2. Anti-IL-8 reversed the decrement in proliferation of clone 2B2 by 50%, but recombinant IL-8 decreased the proliferation of 3B4 by 40-55% compared with control. In addition to A549, three other non-small cell lung cancer (NSCLC) lines showed significantly decreased proliferation in response to exogenous recombinant IL-8 (5-30 ng/ml; p < 0.05). These findings suggest that in addition to its chemotactic and angiogenic activities, IL-8 may inhibit lung tumor proliferation by both autocrine and paracrine pathways.

Macrophage-like-cell-induced growth regulation of lymphoma cells.

Since hematopoietic stromal cells play a major role in regulating the growth and differentiation of hematopoietic cells, we have studied the effects of stromal cells on the in vitro growth of highly malignant murine RAW117-H10 lymphoma cells. These cells, when grown on a preformed layer of syngeneic Balb/c macrophage/monocyte cell line, J774A.1, stop proliferating 48 h after coculture. This stromal-cell-mediated growth regulation appears to require cell-to-cell contact between stromal cells and RAW117-H10 cells, since the J774A.1 cell supernatant did not significantly inhibit the in vitro growth of RAW117-H10 cells. Because one of the cytokines produced by the macrophages is tumor necrosis factor (TNF)-alpha, which is known to inhibit certain tumor cells, we also studied the effects of various concentrations of TNF-alpha on the in vitro growth of RAW117-H10 lymphoma cells. TNF-alpha did not significantly affect the growth of these cells in vitro. However, TNF-alpha induced significant morphologic changes in these cells similar to those seen in plasma cytoid differentiation. Thus, our results indicate that the macrophage-like stromal cells regulate the in vitro growth of malignant lymphoma cells, and that direct cell surface contact between stromal and lymphoma cells is necessary for the growth regulation, and the growth inhibition is not due to TNF-alpha secreted by the macrophages. TNF-alpha is associated with differentiation of these lymphoma cells.

Effects of transforming growth factor-beta 1 on human pulmonary adenocarcinoma cell adhesion, motility, and invasion in vitro.

BACKGROUND: Transforming growth factor-beta 1 (TGF-beta 1), a potent growth modulator produced by a variety of tumor cells, as well as by platelets, has pleiotropic effects on cell-extracellular matrix interactions and may influence tumor cell invasion and metastasis. PURPOSE: Our purpose was to characterize the effects of TGF-beta 1 on the adhesion, motility, and invasiveness of a metastatic human pulmonary carcinoma (A549 cell line) in vitro. METHODS: A549 cells were seeded onto type I collagen gels, and invasion over a 9-day period was measured in the presence or absence of TGF-beta 1 (0.1-10 ng/mL). In addition, cell adhesion to substrata coated with type I collagen (1-100 nM) as well as haptotactic migration through filters coated with type I collagen (100 micrograms/mL) were measured following a 24-hour treatment with TGF-beta 1 (1-10 ng/mL). RESULTS: TGF-beta 1 stimulated the invasion of A549 cells into type I collagen gels in a dose-dependent manner. Both the number of cells entering the gel and the depth of invasion into the gel were increased. In addition, the effects of TGF-beta 1 were blocked in a dose-dependent manner by a purified polyclonal IgG against TGF-beta 1 but not by normal rabbit IgG. A549 cell invasion was accompanied by dramatic changes in A549 cell morphology that included the appearance of numerous long pseudopodia, consistent with a change in the motile behavior of these cells. TGF-beta 1 stimulated by approximately fourfold the haptotactic migration of A549 cells on polycarbonate filters coated with type I collagen. The TGF-beta 1-mediated increase in invasion and motility was accompanied by a fourfold increase in A549 cell adhesion to type I collagen. CONCLUSIONS: The results suggest that TGF-beta 1 can influence cellular recognition of extracellular matrix components and can modulate cellular adhesion and migration on these components, leading to increased invasive potential. IMPLICATIONS: Given the wide-spread tissue distribution of TGF-beta 1 and its secretion by a variety of tumor cells as well as by platelets, TGF-beta 1 may be an important autocrineparacrine regulator of the invasive phenotype in vivo.