CD4 ؉ CD25 ؉ regulatory T cells (Tregs) control immune responses to self-and foreign antigens and play a pivotal role in autoimmune diseases, infectious and noninfectious inflammation, and graft rejection. Since recent experimental studies have indicated that Tregs were able to ameliorate graft-versus-host disease (GvHD), we analyzed the number of infiltrating Tregs in the intestinal mucosa as one site of GvH reactivity using immunoenzymatic labeling to enumerate IntroductionDespite the prophylactic use of potent immunosuppressants, severe graft-versus-host disease (GvHD) is-besides infections-the most relevant complication after allogeneic stem cell transplantation. Immunologically, acute GvHD is characterized by an expansion of donor lymphocytes with cytotoxic reactivity against recipient histocompatibility antigens. The resulting clinical picture includes life-threatening destruction of skin, gut, and liver tissue.In acute GvHD, the transferred immune system lacks the capability to gain control over alloreactive T-cell clones. Therefore, the understanding of mechanisms by which an organism controls allo-or autoimmune reactivity is crucial for the development of successful strategies to prevent and/or control GvHD. Recently, these mechanisms have been further elucidated by the description of a distinct CD4 ϩ T-cell population with the capability to confer nonresponsiveness to T cells against autologous and allogeneic antigens. [1][2][3] These suppressor or regulatory T cells were originally described as a lymphocyte subset that prevents autoimmunity caused by neonatal thymectomy in mice 1 and are characterized by the expression of the interleukin-2 (IL-2) receptor ␣-chain (CD25). More recently, FOXP3, which encodes for a forkhead/winged helix transcription factor called Scurfin, has been identified to be a key regulatory gene required for the development and functional activity of regulatory T cells. [4][5][6][7] Tregs are able to suppress CD4 ϩ and CD8 ϩ T-cell responses to auto-and alloantigens in a contactdependent fashion. 8 In animal models, they can prevent graft rejection 2,3,9 and autoimmune diseases, 8,10 and there is also evidence that inappropriate numbers of Tregs may contribute to the development of chronic inflammatory diseases. 11 Consequently, the question has been raised whether Tregs are also capable of suppressing GvHD. Indeed, it has been shown in different murine models that freshly isolated or ex vivo-expanded donor-type CD4 ϩ CD25 ϩ Tregs are able to delay or even prevent GvH reactivity. [12][13][14][15] Consistent with this, the selective depletion of Tregs leads to an increased severity of acute GvHD in vivo. 16 In humans, however, available data are ambiguous. Whereas Clark et al found elevated numbers of CD4 ϩ CD25 high cells in the peripheral blood of patients with chronic GvHD, 17 Miura et al observed a significantly decreased FOXP3 mRNA expression in the peripheral blood of patients suffering from allogeneic or autologous GvHD. 18 Since the presence of Tregs in the peripheral blo...
Summary:Steroid-resistant acute GVHD (aGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT) continues to be associated with a high mortality. We report the results of a phase II study of treatment of steroid-resistant aGVHD with the IL-2 receptor antibody daclizumab combined with the TNFreceptor fusion protein etanercept. Treatment consisted of daclizumab 1 mg/kg given i.v. on days 1, 4, 8, 15, 22 and etanercept 16 mg/m 2 s.c. on days 1, 5, 9, 13, 17. A total of 21 patients (age 15-61 years) with steroid-resistant aGVHD after alloHSCT were included in the study. Donor types were HLA-matched related (n ¼ 6), HLAmatched unrelated (n ¼ 14), and HLA-mismatched unrelated (n ¼ 1). Eight patients achieved complete, and six showed partial remission of aGVHD. Seven patients did not respond. Four of 21 patients are currently alive with a median follow-up of 586 (185-1155) days. Three patients died due to relapsed malignancy. Treatment-related mortality was due to infectious complications (n ¼ 11) or organ failure due to aGVHD (n ¼ 3). In total, 12 patients developed subsequent chronic GVHD. In conclusion, the data demonstrate an acceptable response rate of the combination of daclizumab and etanercept in the treatment of steroid-resistant aGVHD. Nevertheless, longterm mortality due to infectious complications and chronic GVHD remains high.
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