Quality of life associated with acute and chronic graft-versus-host disease

Acute and chronic graft-versus-host diseases (GVHD) are associated with increased morbidity and mortality after hematopoietic stem cell transplantation (HCT). We prospectively measured the quality of life (QOL) of patients undergoing allogeneic transplantation. Ninety-six subjects completed self-assessment surveys before HCT, and at 6 and/or 12 months post-HCT that included the Medical Outcomes Study Short Form 12 (SF12) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale. Eighty-three percent of survivors responded at 6 and 12 months. Physical and mental functioning assessed by the SF12 was not associated with either acute or chronic GVHD. In contrast, the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant was sensitive to occurrence of either acute or chronic GVHD. GVHD is a major determinant of the long-term QOL of survivors. The adverse effects of acute GVHD are detectable with the TOI at 6 months post transplantation after which development of chronic GVHD is the most strongly correlated with worse QOL.     

Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs

In acute graft-versus-host disease (aGVHD), donor T cells attack the recipient's gastrointestinal tract, liver, and skin. We hypothesized that blocking access to distinct lymphoid priming sites may alter the specific organ tropism and prevent aGVHD development. In support of this initial hypothesis, we found that different secondary lymphoid organs (SLOs) imprint distinct homing receptor phenotypes on evolving alloreactive effector T cells in vivo. Yet preventing T-cell entry to specific SLOs through blocking monoclonal antibodies, or SLO ablation, did not alter aGVHD pathophysiology. Moreover, transfer of alloreactive effector T cells into conditioned secondary recipients targeted the intestines and liver, irrespective of their initial priming site. Thus, we demonstrate redundancy of SLOs at different anatomical sites in aGVHD initiation. Only prevention of T-cell entry to all SLOs could completely abrogate the onset of aGVHD.     

Bullous pemphigoid associated with acute graft-versus-host disease after allogeneic bone marrow transplantation.

A 47-year-old patient was treated with allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia in blast crisis. Three months after the procedure he developed bullous pemphigoid (BP) and symptoms suggestive of BP oesophageal involvement, associated with skin and liver acute graft-versus-host disease. The occurrence of BP is exceptional after BMT.     

Prophylaxis of graft-versus-host disease with cyclosporine-prednisone is associated with increased risk of chronic graft-versus-host disease

To determine the effect of two different graft-versus-host disease (GVHD) prophylactic regimens--cyclosporine with short course of methotrexate (CYA-MTX) and cyclosporine with prednisone (CYA-PRED)--on the incidence of chronic GVHD (cGVHD), we retrospectively reviewed the outcomes of 196 consecutive allogeneic related blood and marrow transplants performed at our institution utilizing one of these regimens. CYA-PRED was given to patients who were transplanted more recently because of concern about the increased risk of veno-occlusive disease of the liver, increased mucositis, and slower engraftment in patients receiving CYA-MTX. Prophylaxis with CYA-PRED was associated with a higher risk of development of cGVHD (risk ratio (RR) 3.5; 95% confidence intrerval (CI), 2.2-5.4). The proportion of patients with extensive disease among those developing cGVHD was higher in the CYA-PRED group (71%) than in the CYA-MTX group (57%), although this difference was not statistically significant. The cumulative probability of extensive cGVHD at 2 years was higher in the CYA-PRED group (RR 4.2, 95% CI, 2.4-7.4). Development of acute GVHD and cytomegalovirus mismatch were independent predictors of increased risk of cGVHD. We conclude that GVHD prophylaxis with CYA-PRED is associated with a higher overall rate of cGVHD compared to CYA-MTX. The type of GVHD prophylaxis should be considered when comparing the incidence of cGVHD reported in different studies.     

Cellular infiltrates in scleroderma skin

The purpose of this study was to determine the frequency, distribution, and nature of cellular infiltrates in 108 skin biopsies from patients with systemic scleroderma (SS) and localized scleroderma (LS). Cellular infiltrates, perivascular or diffuse, were noted in 49% of SS and 84% of LS patients and consisted of lymphocytes, plasma cells, and macrophages. No correlation was noted between the presence or severity of skin cellular infiltrates and serum serologic abnormalities.     

Immunobiology of acute graft-versus-host disease

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The immunobiology of acute GVHD is complex and can be conceptualized to be a three-step process. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines TNF-alpha and IL-1. As a consequence expression of MHC antigens and adhesion molecules is increased, thus enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T-cell interaction with host APCs and subsequent proliferation, differentiation, and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses, and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host.     

Management of acute graft-versus-host disease

Acute graft-versus-host disease (GvHD) is a frequent complication of allogeneic haemopoietic stem cell transplantation (HSCT) and donor lymphocyte infusions (DLI). Its incidence and severity depends on several factors, such as prophylaxis method, donor/recipient matching, intensity of the conditioning regimen and composition of the graft. Significant progress has been made in recent years in understanding the pathogenesis of the disease, and some of these advances have been translated into clinical trials. First-line treatment of acute GvHD is based on corticosteroids, and produce sustained responses in 50-80% of patients depending on the initial severity. Non-responders are offered second-line therapy, with combinations of immunosuppressive agents, but 1-year survival is 30% in most large trials. New strategies explored include infusion of expanded mesenchymal stem cells (MSC), down regulation of antigen-presenting cells (APC) and suicide gene transduced T cells. Acute GvHD is complicated by severe immunodeficiency causing life-threatening infections. To date, GvHD has not been differentiated from the graft-versus-leukaemia effect. The present review will discuss some of these aspects.     

Management of acute graft-versus-host disease

Current graft-versus-host disease (GVHD) prophylaxis is not uniformly successful. Since the development of GVHD has a profound impact on transplant success, treatment is required. The mainstay of therapy has been glucocorticoids (steroids), along with anti-thymocyte globulin, cyclosporine, monoclonal antibodies, and aggressive supportive care, resulting in response rates of 30-50%, dependent upon severity of the disease, type of transplant, underlying diagnosis, prophylaxis given and other factors. Dose intensification or combinations of agents may increase response rates (60-80%), however, without necessarily improving survival, due to intervening complications. Nevertheless, patients with complete responses have a higher probability of survival, and a subgroup of patients will not develop chronic GVHD. As our understanding of cell recruitment, cell interactions and cytokine networks improves, new strategies are likely to be developed. The sequential use of antibodies directed at different cell populations or cytokines, along with anti-inflammatory measures, may be helpful. Prevention of GVHD has to remain our objective; however, efforts at therapy must continue until that goal is achieved.     

Advances in the understanding of acute graft-versus-host disease

Allogeneic stem cell transplantation (SCT) remains the definitive immunotherapy for malignancy. However, morbidity and mortality due to graft-vs.-host disease (GVHD) remains the major barrier to its advancement. Emerging experimental data highlights the immuno-modulatory roles of diverse cell populations in GVHD, including regulatory T cells, natural killer (NK) cells, NK T cells, gammadelta T cells, and antigen presenting cells (APC). Knowledge of the pathophysiology of GVHD has driven the investigation of new rational strategies to both prevent severe GVHD and treat steroid-refractory GVHD. Novel cytokine inhibitors, immune-suppressant agents known to preserve or even promote regulatory T-cell function and the depletion of specific alloreactive T-cell sub-populations all promise significant advances in the near future. As our knowledge and therapeutic options expand, the ability to limit GVHD whilst preserving anti-microbial and tumour responses becomes a realistic prospect.     

Moderate hyperprolactinemia is associated with survival in patients with acute graft-versus-host disease after allogeneic stem cell transplantation

Abstract

Fasting serum prolactin (PRL) levels in response to metoclopramide (MCP) and lymphocyte cytokine profiles was studied in patients given allografts and their donors. Thirty normoprolactinemic volunteers (12–59 years) were studied: group 1, 10 healthy men; group 2, 8 males and 2 females with various hematologic diseases; and group 3, 3 males and 7 females HLA-identical sibling donors: PRL and cytokines were measured. Four surviving recipients developed acute graft-versus-host disease (GVHD) (+), and six did not.

Before transplant

Fasting PRL concentrations were higher in ‘future’ GVHD(+) recipients than in their donors (P < 0.001). The opposite was seen in response to MCP (P = 0.01). Donors had a predominant T-helper type 1 (Th1) cytokine profile compared with recipients (P ≤ 0.02), and GVHD(+) recipients had a greater tumor necrosis factor (TNF) value than GVHD(?) (P = 0.05).

After transplant

On days +30 and +100, a mild sustained rise in fasting PRL levels occurred only in GVHD(+) recipients (P ≤ 0.05) simultaneously with a transient rise in Th1 cytokines. GVHD(?) recipients had no changes. Donors with a Th1 cytokine profile might be more prone to induce GVHD in their recipients, and a mild sustained rise in PRL concentrations after transplantation in recipients GVHD(+) might participate in the amelioration of the severity of GVHD.     

Moderate hyperprolactinemia is associated with survival in patients with acute graft-versus-host disease after allogeneic stem cell transplantation

Fasting serum prolactin (PRL) levels in response to metoclopramide (MCP) and lymphocyte cytokine profiles was studied in patients given allografts and their donors. Thirty normoprolactinemic volunteers (12-59 years) were studied: group 1, 10 healthy men; group 2, 8 males and 2 females with various hematologic diseases; and group 3, 3 males and 7 females HLA-identical sibling donors: PRL and cytokines were measured. Four surviving recipients developed acute graft-versus-host disease (GVHD) (+), and six did not. Before transplant Fasting PRL concentrations were higher in 'future' GVHD(+) recipients than in their donors (P < 0.001). The opposite was seen in response to MCP (P = 0.01). Donors had a predominant T-helper type 1 (Th1) cytokine profile compared with recipients (P ≤ 0.02), and GVHD(+) recipients had a greater tumor necrosis factor (TNF) value than GVHD(-) (P = 0.05). After transplant On days +30 and +100, a mild sustained rise in fasting PRL levels occurred only in GVHD(+) recipients (P ≤ 0.05) simultaneously with a transient rise in Th1 cytokines. GVHD(-) recipients had no changes. Donors with a Th1 cytokine profile might be more prone to induce GVHD in their recipients, and a mild sustained rise in PRL concentrations after transplantation in recipients GVHD(+) might participate in the amelioration of the severity of GVHD.     

Efficient identification of T-cell clones associated with graft-versus-host disease in target tissue allows for subsequent detection in peripheral blood

Graft-versus-host disease (GVHD) causes severe morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) because of destruction of recipient tissues by donor alloreactive T cells. We hypothesized that GVHD-specific T-cell clones are expanded within affected tissue of HSCT patients and can also be detected in blood at the time of active disease. A multiplex polymerase chain reaction (PCR) was used to amplify T-cell receptor (TCR) variable beta (VB) chain rearrangements in skin biopsies from eight allogeneic HSCT patients. Molecular analysis of the complementarity-determining region 3 (CDR3) of amplified products defined expanded, potentially disease-associated 'clonotypes' and enabled the design of clonotype-specific PCR assays. We detected immunodominant clones in seven of eight GVHD-positive skin biopsies. In serial skin biopsies from the same patient, the identical clone was found in each biopsy. In a patient who underwent two successive HSCTs from different donors, distinct clones were identified for each engraftment. Using clonotypic PCR assays, individual tissue-derived clones could be identified in peripheral blood samples obtained during active GVHD. We hypothesize that clonotypic sequences derived from target tissue can serve as markers for GVHD and may have utility in diagnosis and monitoring response to therapy, as well as enable future therapies targeted against pathogenic clones.     

Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level

Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.     

Expression of CD30 in patients with acute graft-versus-host disease

Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8(+) T cells with the difference especially pronounced in the central memory subset (CD8(+)CD45RO(+)CD62L(+)): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4(+) T cells, and regulatory (CD4(+)CD127(low)CD25(+)) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30(+) infiltrating lymphocytes present. These results suggest that CD30 expression on CD8(+) T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD.