Acute graft-vs-host disease. Development following autologous and syngeneic bone marrow transplantation

Summary:Cyclosporin A (CsA) can induce graft-versus-host disease (GVHD) following autologous bone marrow transplantation (ABMT) and autologous peripheral blood stem cell transplantation (APBSCT) in adults. We investigated whether GVHD can be induced following ABMT and APBSCT in childhood, and which cells are involved in the pathogenesis of this syndrome. We conducted a prospective study of 20 children and adolescents with hematological malignancies receiving CsA after ABMT and APBSCT. Skin biopsies were obtained on day 21 after transplantation or in the event of a rash. Immunophenotypic analysis of peripheral blood lymphocytes was performed on days 14, 21, 28 and 60 after transplantation. Clinical GVHD of the skin, confirmed by histological criteria, occurred in five patients. Five patients had no clinical GVHD but had acute GVHD alterations on routine skin biopsy. In all 10 patients with a positive skin biopsy for GVHD, CD4 + lymphocytes were the predominant cells in the epidermis. Immunophenotypic analysis of peripheral blood lymphocytes revealed a significantly increased CD4/CD8 ratio in patients with a positive skin biopsy (P Ͻ 0.01). Our findings indicate that it is possible to induce acute GVHD following ABMT and APBSCT in childhood. In addition, CD4 + lymphocytes play an important role in the pathogenesis of CsA-induced GVHD. Keywords: cyclosporin A; graft-versus-host disease; bone marrow transplantation; hematopoietic stem cell transplantation Despite the increased morbidity and mortality in patients with graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), GVHD is associated with a clinically significant antitumor effect. 1,2 It has been shown that mature T cells from the donor contaminating the bone marrow inoculum are responsible for the development of GVHD. 3 T cell depletion of donor marrow for allogeneic BMT leads to a markedly reduced incidence of GVHD in the marrow recipients. Unfortunately, T cell depletion is also associated with an increased incidence of marrow graft failure and an increase in relapse rate. 4 The procedure-related toxicity is lower after autologous bone marrow transplantation (ABMT) than after allogeneic BMT. In contrast, the higher relapse rates after autologous and syngeneic BMT than after allogeneic BMT are at least partly due to the absence of graft-versus-tumor effect associated with GVHD. 5,6 A syndrome that clinically resembles acute GVHD has been observed spontaneously in 8% of patients receiving autologous or syngeneic BMT. 7 This syndrome appears to involve only the skin, is generally mild, and is self-limiting. Due to the rarity of this phenomenon, it has not been possible to determine its effects on leukemic relapse rates.In ABMT, further significant dose escalation with the current conditioning protocols is limited due to unacceptable toxicity. Therefore, interest has focused on methods stimulating immunologically mediated antitumor activity. In animal models, GVHD was induced by treatment with cyclosporin A (CsA) in rats or mice un...

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confidence: 99%

Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Gruhn

Häfer

Kosmehl³

et al. 1998

“…These two patients could represent mild 'autologous GVHD', which is generally less severe than allogeneic GVHD. 33 Similarly, one autologous BMT recipient showed increased keratinocyte apoptosis in the presence of increased epidermal lymphocytes, suggesting a possible cytokine-mediated autologous GVHD. We interpret the apoptotic keratinocytes in the other autologous BMT recipients (who had few epidermal lymphocytes and no TIA-1 caps) to represent the effects of conditioning regimens.…”

Section: Discussionmentioning

confidence: 99%

Keratinocyte apoptosis following bone marrow transplantation: evidence for CTL-dependent and -independent pathways

Conyers

et al. 1998

Summary:Acute graft-versus-host disease (GVHD) is a complication of bone marrow transplantation (BMT). The histopathologic features used to diagnose GVHD are nonspecific, and may be secondary to chemotherapy or irradiation given before BMT. The presence of apoptotic keratinocytes or activated CTL may distinguish GVHD from conditioning effects. This study investigated the relationship in BMT recipients between keratinocyte apoptosis and the effects of conditioning regimens or immune-mediated GVHD. Inflammatory cells, apoptotic keratinocytes, and CTL expressing TIA-1 (a molecule associated with the lytic granules of CTL) were quantitated in allogeneic and autologous recipients. Allogeneic recipients could exhibit keratinocyte apoptosis secondary to a combination of conditioning effects and immune-mediated GVHD. In contrast, autologous recipients should show conditioning effects only. 'Capped' TIA-1-positive lymphocytes and apoptotic keratinocytes were much more frequent in the allogeneic group than the autologous group (16.1% of total TIA-1 positive lymphocytes vs 4.5%, P = 0.02; and 37.6/mm 2 vs 3.9/mm 2 , P = 0.005, respectively), although there was some overlap in their frequency. Among individual recipients of allogeneic BMT, the number of epidermal lymphocytes or macrophages correlated with the number of apoptotic keratinocytes. A similar, but weaker, correlation was seen between the number of 'capped' TIA-1-positive lymphocytes and apoptotic keratinocytes. No such relationship was seen in autologous recipients. In allogeneic recipients, TIA-1 expressing CTL were seen in intimate contact with apoptotic keratinocytes, some of which also had detectable cytoplasmic TIA-1. No CTL/keratinocyte interactions were identified in autologous recipients. Our results suggest that apoptotic keratinocytes arise in the skin of BMT patients due to both GVHD and conditioning effects, and that the keratinocyte damage in GVHD is mediated by both CTL-dependent and -independent mechanisms. Increased numbers of apoptotic keratinocytes, in the presence of increased epidermal lymphocytes or 'capped' TIA-1-expressing lymphocytes, support a diagnosis

“…Acute skin GVHD is described in the context of autologous and syngeneic BMT. 3,[5][6][7][8][9][10] The mechanism is thought to be release of autoreactive T cells directed at HLA class II antigens 2,11,12 by failure of apoptotic deletion due to thymic damage by TBI. 13,14 This mechanism may be enhanced by CYA which breaks selftolerance 15 and has been used to induce autologous GVHD.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Mild and self-limiting acute skin GVHD is thought to occur in 8% of patients receiving autologous and syngeneic BMT. 3 …”

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confidence: 99%

Acute skin GVHD following syngeneic BMT for CLL

Deane

Singer

Lawler

et al. 1998

Summary:A 41-year-old woman received a syngeneic BMT for CLL and subsequently developed acute skin GVHD. Transfusion-related allogeneic GVHD was excluded on the basis of an unchanged HLA type in circulating lymphocytes. Short tandem repeat PCR was used to confirm syngeneicity between donor and recipient. The patient had a personal and family history of autoimmune disease which may have made her particularly susceptible to development of syngeneic GVHD. The distinction between allogeneic and syngeneic or autologous GVHD is important because of therapeutic implications. Keywords: GVHD; syngeneic BMT; CLL; chimerism We report the case of a 41-year-old woman who received a syngeneic BMT for CLL and subsequently developed histologically proven acute grade 2 skin GVHD requiring treatment, including high-dose corticosteroids. The HLA type of circulating lymphocytes remained unchanged. Short tandem repeat (STR)-PCR analysis of pre-BMT DNA extracted from donor and recipient indicated identity between donor and recipient supporting the diagnosis of syngeneic GVHD. Syngeneic and autologous GVHD has been described in animal models. 1,2 Mild and self-limiting acute skin GVHD is thought to occur in 8% of patients receiving autologous and syngeneic BMT. 3 Case reportThe patient presented with stage B CLL and Sjogren's syndrome in 1992. There was a strong family history of autoimmune disease. The patient, her mother and identical twin sister all had hypothyroidism and the patient's mother also had SLE. The patient required intermittent treatment for CLL but, by 1994, her disease had advanced to cause bone marrow failure. She showed a good response to six courses of fludarabine with a reduction in bone marrow lymphocytic infiltration to 40%. She subsequently received a syngeneic BMT following CY 120 mg/kg and single fraction TBI (750 cGy at 16 cGy/min) conditioning. Both recipent and donor were CMV seronegative. At the time of transplant, the patient had no evidence of active autoimmune disease. She received irradiated blood products throughout. The transplant was uncomplicated with haemopoietic recovery (Ͼ0.5 × 10 9 /l neutrophils, Ͼ20 × 10 9 /l platelets) at day 25. Over the next week she developed a generalised skin rash which progressed to desquamation. She was systemically well with no evidence of infection. She had not been commenced on any new drugs in the preceding 3 weeks. A skin biopsy showed the appearances of grade II GVHD with basal cell degeneration and a focal lymphocytic infiltration of the epidermis (Figure 1). Although the patient had been designated to receive irradiated blood products, and showed no deterioration in bone marrow function, we felt that transfusion acquired GVHD should be excluded because of therapeutic implications. The HLA type of the circulating lymphocytes was determined and was unchanged. Pre-BMT DNA extracted from the recipient and donor was compared using a panel of STR markers as previously described. 4 Seven markers were tested (see