Serum transforming growth factor-beta1 levels in bone marrow transplant recipients correlate with blood cell counts and chronic graft-versus-host disease.

OBJECTIVE: Profound immunosuppression and extensive fibrotic changes in the skin are characteristic for graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Transforming growth factor (TGF)-beta is a potent immunosuppressive cytokine that plays an important regulatory role in the immune response. In addition, TGF-beta promotes wound repair but has also been implicated in tissue fibrosis. These characteristics prompted us to question whether serum TGF-beta levels would be associated with GVHD after BMT. METHODS: In this study, total TGF-beta1 levels in serum from HLA-identical BMT recipients before and at several time intervals after transplantation were quantified and correlated with platelet and white blood cell (WBC) counts and with the presence of acute and chronic GVHD in a multivariate analysis. RESULTS: TGF-beta1 levels were readily detectable in healthy controls and in BMT recipients before BMT. In all patients, a rapid drop in TGF-beta1 levels was seen during the BMT conditioning regimen. After 20-50 days postBMT, TGF-beta1 levels started to increase to normal levels. Platelet and WBC counts were strongly correlated with TGF-beta1 levels (r=0.810, P<0.001, and r=0.733, P<0.001, respectively). Multivariate analysis also revealed that TGF-beta1 levels were significantly increased during chronic GVHD and that the increase during acute GVHD reached levels of significance (P=0.009 and P=0.053, respectively). CONCLUSIONS: These results show that total TGF-beta1 levels correlate significantly with platelet and WBC counts and that chronic GVHD is associated with an increase in serum TGF-beta1, independent of platelet or WBC counts.

Serum cytokine levels after HLA-identical bone marrow transplantation.

BACKGROUND: Altered profiles of cytokine production are observed after bone marrow transplantation (BMT). The presence of certain cytokines in serum can be indicative for BMT-related complications, such as graft-versus-host disease (GVHD) and infections. The putative correlation between abnormal serum cytokine levels and BMT-related complications was further analyzed in this retrospective study. METHODS: Serum levels of a panel of cytokines and cytokine-associated molecules (i.e., interleukin [IL]-1alpha, IL-1beta, IL-4, IL-6, IL-10, IL-12, IL-1 receptor antagonist, and the soluble a chain of the IL-2 receptor [sIL-2R alpha]) were assessed in 329 sera of 46 patients who had undergone HLA-identical or autologous BMT. Serum cytokine levels of the BMT donor and of the patients before BMT and at different time points during the post-BMT period were measured. The results were correlated with relapse, acute GVHD, chronic GVHD, and infections. RESULTS: Serum levels of IL-1alpha, IL-1beta, IL-4, and IL-12 were undetectable. The transplantation regimen itself causes a significant rise in IL-10 and sIL-2R alpha levels in patients receiving allogeneic bone marrow. In the post-BMT period, increased IL-6 serum levels were significantly correlated with infections. Increased IL-10 levels were significantly correlated with acute graft-versus-host disease, chronic GVHD, and infections. Increased sIL-2R alpha levels were correlated with chronic GVHD, as were IL-1 receptor antagonist levels. CONCLUSIONS: During the post-HLA-identical BMT period, the serum cytokine levels of IL-6 were enhanced during infections, whereas the sIL-2R alpha levels were increased during chronic GVHD. The serum levels of IL-10 and of the cytokine-related molecule IL-1ra were enhanced during both infections and chronic GVHD. These results further substantiate the complex cytokine cascade that is initiated by the conditioning regimen and that evolves further in reaction to BMT-related complications and their treatments.

Soluble Fas levels in sera of bone marrow transplantation recipients are increased during acute graft-versus-host disease but not during infections.

Graft-versus-host disease (GVHD) and infections are two major complications of allogeneic bone marrow transplantation (BMT). In the course of GVHD, one of the pathways that activated cytotoxic T cells use to execute their killing mechanisms is the Fas/Fas ligand pathway. This killing mechanism might be accompanied by the release of soluble Fas (sFas) in the circulation. To examine the association of serum sFas levels and post-BMT complications, we have analyzed sFas levels in sera of bone marrow recipients with and without GVHD. Postallogeneic BMT sFas levels were significantly increased during clinically relevant acute GVHD (aGVHD; P = .002). However, during infections sFas levels tended to decrease (P = .088). Yet, the simultaneous occurrence of GVHD and infections resulted in extreme high sFas levels. These results suggested that sFas release may be correlated with the amount of tissue damage, because aGVHD induces more damage than infections. The presence of significantly increased sFas levels during aGVHD provides new insights into the GVHD pathogenesis.

Elevated serum HLA class I levels coincide with acute and chronic graft-versus-host disease.

The ability to predict the likely occurrence of graft-versus-host-disease (GVHD) after BMT would be extremely valuable. We performed a retrospective study on the correlation between soluble HLA class I (sHLA-I) levels and GVHD in the sera of 34 patients receiving an allogeneic BMT and in the sera of 12 patients receiving an autologous BMT. sHLA-I levels measured pre- and at different times post-BMT were correlated with the occurrence of post-BMT complications, ie acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), infections and relapse. No changes in sHLA-I levels (delta sHLA-I) occurred in autologous and allogeneic BMT patients without GVHD. In contrast, sHLA-I reached high levels in patients suffering from GVHD. Increased sHLA-I levels correlated strongly with episodes of both acute and chronic GVHD (P = 0.004 and P = 0.005, respectively). Also during relapse increased sHLA-I levels were found (P = 0.032). During infections sHLA-I levels increased, although not significantly. Kinetic studies gave no evidence that the increase in sHLA-I levels preceded the clinical occurrence of aGVHD or of cGVHD. A slight, but significant correlation was found between total blood bilirubin levels and sHLA-I levels in patients suffering from GVHD (P = 0.037), indicating the contribution of the liver as a source of sHLA-I. We conclude that measurements of sHLA-I levels do not function as a predictive parameter for GVHD, but can be valuable for the monitoring of GVHD after BMT.

Anti-host cytotoxic T cells of bone marrow transplant recipients with or without graft-versus-host disease are equally sensitive to cyclosporin A.

It is generally accepted that cytotoxic T cells (CTLs) play an important role in the pathogenesis of graft-versus-host disease (GVHD). Nonetheless, anti-host CTLs can be observed in the peripheral blood of patients both with and without clinical signs of GVHD following HLA genotypically identical bone marrow transplantation. Thus we questioned whether a qualitative difference, such as a differential in vitro sensitivity to cyclosporin A (CsA), may exist between the anti-host CTLs, generated from these groups of patients post-bone marrow transplantation (BMT). We analyzed anti-host CTL precursors (CTLp) of patients without clinical signs of GVHD, of patients suffering from acute GVHD (grade II-IV) and of patients suffering from acute GVHD followed by chronic GVHD for their in vitro sensitivity to the inhibitory effects of CsA. The results obtained in a total of 20 patients revealed anti-host CTLp frequencies (CTLpf) post-BMT in all three groups of patients and addition of CsA in the tests resulted in approximately 60% inhibition of the CTLpf independent of the GVHD status of the patients. Thus, in view of the in vitro CsA sensitivity, no difference exists between the anti-host CTLs in patients with or without GVHD.