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Pavan Reddy

Publications and source records attributed to Pavan Reddy.

25 records · Page 2Linked to original sources
PubMed2003

Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody.

We reviewed the clinical outcome of 8 patients with steroid-refractory chronic graft-versus-host disease (GVHD) who received an anti-CD20 chimeric monoclonal antibody (rituximab). Rituximab was given by intravenous infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients had received extensive treatment with various immunosuppressive agents; 6 patients had also received extracorporeal photopheresis. All patients had extensive chronic GVHD with diffuse or localized sclerodermoid GVHD and xerophthalmia. Other extracutaneous involvements included cold agglutinin disease with the Raynaud phenomenon, membranous glomerulonephritis, and restrictive or obstructive lung disease. Four patients responded to treatment with ongoing resolution or improvement ranging from 265 to 846 days after therapy, despite recovery of B cells in 3 patients. Rituximab seems to have significant activity in the treatment of refractory chronic GVHD and should be considered for further study in patients with early disease. This study suggests a participating role of B cells in the pathogenesis of chronic GVHD.

Adult↗
PubMed2002

Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects.

Interleukin-18 (IL-18) is a unique cytokine that modulates both T(H)1/T(H)2 responses, but its ability to modulate diseases through induction of T(H)2 cytokines is unclear. It has been shown to play an important role in allogeneic bone marrow transplantation (BMT). Because immune responses of allogeneic BM donors may affect acute graft-versus-host disease (GVHD), we investigated the effect of pretreating BM transplant donors with IL-18 on the severity of acute GVHD using a well-characterized experimental BMT model (BALB/c-->B6). Pretreatment of allogeneic BM transplant donors with IL-18 significantly improved survival (80% vs 0%; P <.001), and reduced clinical, biochemical, and pathologic indices of acute GVHD in BM transplant recipients. IL-18 pretreatment was associated with reduced interferon gamma (IFN-gamma) and greater IL-4 secretion by donor T cells after BMT. Acute GVHD mortality was reduced when IL-18 was administered to donors deficient in IFN-gamma and signal transducer and activator of transcription 4 (STAT4) but not STAT6 signaling molecules, suggesting a critical role for STAT6 signaling in IL-18's protective effect. IL-18 treatment did not alter donor CD8(+) cytotoxic T-lymphocyte (CTL) activity and preserved graft-versus-leukemia (GVL) effects after allogeneic BMT (70% vs 10%; P <.01). Together these data illustrate that pretreatment of donors with IL-18 prior to allogeneic BMT attenuates acute GVHD in a STAT6-dependent mechanism while preserving GVL effects.

Acute Disease↗
PubMed2002

Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation.

We have recently shown that early administration of interleukin 18 (IL-18) after bone marrow transplantation (BMT) attenuates acute graft-versus-host disease (GVHD) in a lethally irradiated parent into F1 (B6-->B6D2F1) BMT model. In this study, we investigated whether IL-18 can maintain graft-versus-leukemia (GVL) effect in this context. B6D2F1 mice received transplants of T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either syngeneic (H2(b/d)) or allogeneic B6 (H2(b)) donors. Recipient mice were treated with recombinant murine IL-18 or the control diluent. Initial studies demonstrated that IL-18 treatment did not affect the proliferative responses or the cytolytic effector functions of T cells after BMT. In subsequent experiments, animals also received host-type P815 mastocytoma cells at the time of BMT. All syngeneic BM transplant recipients died from leukemia by day 18. The allogeneic BM transplant recipients effectively rejected their leukemia regardless of treatment and IL-18 significantly reduced GVHD-related mortality. Examination of the cytotoxic mechanisms with perforin-deficient donor T cells demonstrated that perforin is critical for the GVL effect. Taken together these data demonstrate that IL-18 can attenuate acute GVHD without impairing the in vitro cytolytic function or the in vivo GVL activity after allogeneic BMT.

Animals↗
PubMed2002

Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8 alpha(+) dendritic cells and reduces experimental acute graft-versus-host disease.

Recent evidence suggests that dendritic cells (DCs) can regulate and amplify immune responses. Flt3 ligand (FL)-derived DC function was tested as a stimulator of allogeneic lymphocytes in vitro and in vivo. Treatment of mice with FL dramatically expanded DC number, but DCs isolated from FL-treated mice (FL DCs) were poor stimulators of allogeneic T-cell responses in vitro. Further activation of FL DCs did not restore their stimulatory ability, and FL DCs did not suppress the stimulation of the allogeneic T cells by normal DCs. FL treatment significantly increased the CD8 alpha(+) DC subset, which appeared to be the reason for their poor stimulatory capacity. These observations were confirmed in vivo using a mouse model of acute graft-versus-host disease (GVHD) wherein host DCs play a critical role. FL treatment of recipients before allogeneic bone marrow transplantation dramatically suppressed donor T-cell responses to host antigens, thereby reducing GVHD mortality (P <.01). These data represent a novel strategy that alters host DCs and reduces acute GVHD.

Acute Disease↗
PubMed2002

Acute graft-versus-host disease does not require alloantigen expression on host epithelium.

Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.

Acute Disease↗
PubMed2002

Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease.

Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.

Aging↗