Immunopathology of Early Graft-Versus-Host Disease—a Prospective Study of Skin, Rectum, and Peripheral Blood in Allogeneic and Autologous Bone Marrow Transplant Recipients

Sviland, Lisbet; Pearson, Andrew D.J.; Green, Malcolm A.; Baker, B; Eastham, Edmund J.; Reid, M M; Hamilton, Peter J.; Proctor, Stephen J.; Malcolm, A. J.

doi:10.1097/00007890-199112000-00018

Cited by 26 publications

(14 citation statements)

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“…Similar findings have been previously reported. [24][25][26] However, a comparable increase in the number of infiltrating CD8 ϩ cells was also observed in patients with other inflammatory conditions such as CMV-colitis ( Figure 1). Therefore, this finding alone is of limited value for the differential diagnosis of GvHD.…”

Section: Increased T-cell Infiltration In the Mucosa Of Patients Withmentioning

confidence: 57%

Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD

Rieger

Loddenkemper

Maul

et al. 2006

Blood

220

144

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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...

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Section: Increased T-cell Infiltration In the Mucosa Of Patients Withmentioning

confidence: 57%

Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD

Rieger

Loddenkemper

Maul

et al. 2006

Blood

220

144

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“…14,[16][17][18]33 There was also a suggestion that ␥/␦ cells plant. 16,26,29,30,32,46,[48][49][50][51][52][53][54] B cell numbers generally recover earlier than T cell levels, 16,32 although their functional were transiently increased shortly following transplantation and that there were abnormalities in the CD45RA and reconstitution, perhaps due to low helper T cell activity, or an oligoclonal expansion 18,38,39 is slower than the recovery CD45RO cell frequencies. 14,55 The data from the present study demonstrates that there is a rapid recovery of lymphoin the frequency or absolute number of B cells.…”

Section: Mitogen Responsementioning

confidence: 99%

Rapid immunologic reconstitution following transplantation with mobilized peripheral blood stem cells as compared to bone marrow

Talmadge

Reed

Ino

et al. 1997

Bone Marrow Transplant

175

142

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Summary:ABMT may contribute to an improved clinical outcome. Further, patients receiving a PSCT may be more A majority of patients with intermediate or high-grade responsive to adjuvant immunotherapy following transnon-Hodgkin's lymphoma (NHL) who are treated with plantation. high-dose chemotherapy (HDT) and hematopoietic stem Keywords: PSCT; BMT; immunity; T cell; NHL; NK cell transplantation subsequently relapse. Until recently, cell F transplantation was associated with high morbidity and mortality and the focus was on improving the safety of this procedure. However, the use of growth factors and other supportive measures has successfully reduced High-dose chemotherapy (HDT) supported by hematopotreatment mortality to less than 5%. Therefore, new ietic stem cell transplantation and growth factor adminisstrategies need to be developed to eliminate the growth tration is increasingly used for patients with cancer. 1-3 Leuof any occult tumor cells reinfused with the stem cell kocyte and platelet recovery is more rapid following products and the tumor cells remaining in the patient.peripheral blood stem cell transplantation (PSCT) as comOne approach is to improve the immune function of the pared to bone marrow autografts (ABMT), if the peripheral patients by a more rapid immune reconstitution and stem cells (PSC) are collected after mobilization with hemaugmentation of effector cell function. We report studatopoietic growth factors, chemotherapy, or both. [4][5][6][7][8] In ies comparing immune recovery following HDT and addition, one retrospective study suggested an increase in autologous peripheral stem cell transplantation (PSCT) the progression-free interval following PSCT with steady as compared to autologous bone marrow transplanstate PSC as compared to ABMT, 9 although this obsertation (ABMT). These studies examined patients with vation requires confirmation as well as demonstration in a intermediate and high-grade non-Hodgkin's lymphoma prospectively randomized trial. 4,10,11 (NHL) who were treated with HDT and PSCT (n = 56) PSCT 6,12 may result in an earlier reconstitution of or ABMT (n = 60). The PSCT patients had a signifiimmune function following HDT as compared to cantly faster recovery of circulating monocytes (CD14 + ABMT 13,14 perhaps due to the lymphocytes that are trans- cells), natural killer ((NK) CD56 + ) cells, T helper (CD4 + )fused in the PSC product. To date, there have been limited cells, TCR␥/␦ cells, and naive T lymphocytes and conflicting studies on immune reconstitution following (CD45RA + ). Following ABMT there was a significantly PSCT and ABMT in humans. [15][16][17][18] Overall, there appears to more rapid increase in the frequency of T be wide phenotypic variability of cells in the suppressor/effector (CD8 + ) cells, B (CD19 + ) cells, CD34 + apheresis/transplant products themselves. 14 A significant cells, polymorphonuclear leukocytes (PMN) and memincrease in the frequency of CD8 + cells in the peripheral ory T lymphocytes (CD45RO + ). The CD4:CD8 and blood (PB) following both f...

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“…Epithelial cells of the skin, gut and liver are predominant targets of T-cell-mediated damage in GVHD, frequently resulting in disease-related morbidity and mortality (Sviland et al, 1999). As epithelial cells lack expression of B7 costimulatory molecules, they cannot activate primary donor T cells, thus it can be envisaged that, after an allogeneic BMT, professional antigen-presenting cells (APCs), such as Langerhans cells, are involved in the initial activation of donor T cells reactive with mHags on patient epithelial cells (van Lochem et al, 1996;Favre et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Helper Tprecursor frequency assays (HTLp-assays) measuring interleukin (IL) 2 production have been used to study donor Tcell recognition of patient MHCs and mHags preceding BMT to predict GVHD (Theobald et al, 1992;Winandy et al, 1999). In these studies, patient peripheral blood mononuclear cells (PBMCs) were used as stimulator cells, although they may not be the most suitable targets when studying GVHD in which epidermal cells of skin, gut and liver are the main targets of T-cell reactivity (Dickinson et al, 1998;Sviland et al, 1999). On the other hand, measurement of primary T-cell responses against epidermal cells such as keratinocytes (KCs) is complicated by the fact that they do not express B7 co-stimulatory molecules, rendering them incapable of stimulating naive T cells .…”

mentioning

confidence: 99%

Determination of helper T‐cell precursor frequencies against non‐haemopoietic cells: comparison of co‐stimulation provided by anti‐CD28 antibody versus the cellular ligand B7‐1

Dijk¹,

Gast

Kessler

et al. 2000

Br J Haematol

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Helper T‐cell precursor frequency assays (HTLp‐assays) are commonly used in transplantation to examine the frequency of T cells reactive against donor or host alloantigens. In these assays, peripheral blood mononuclear cells (PBMCs) are most often used as stimulator cells. However, cells targeted after transplantation do not always belong to the haematopoietic lineage and may express different alloantigens, especially minor histocompatibility antigens (mHags). Non‐haematopoietic cells lack expression of the B7 co‐stimulatory molecules needed to activate primary T cells that can be supplied by anti‐CD28 (αCD28) antibodies or transfection with B7‐1 coding sequences. At present, it is not known how these two ways of supplied co‐stimulation compare in HTLp assays. B7‐1‐transfected A431 keratinocytes (A431B7‐1) induced higher proliferative responses in allogeneic primary T cells and more interleukin (IL) 2 production than that induced by A431 cells plus αCD28, whereas the kinetics of proliferation and IL‐2 production were similar. Neither cross‐linking of αCD28 bound to T cells nor prevention of IL‐2 resorption by the anti‐IL‐2 receptor resulted in improved proliferation or IL‐2 production. Results of HTLp assays indicated that A431B7‐1 activated on average 7·5 times more alloreactive IL‐2‐producing T cells than A431 cells plus αCD28. We conclude that primary T‐cell alloresponses against major histocompatibility complexes (MHCs) and mHags expressed on non‐haematopoietic cells can be measured in HTLp assays using supplied co‐stimulation, although αCD28 yields an intrinsic underestimation of actual frequencies.

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Immunopathology of Early Graft-Versus-Host Disease—a Prospective Study of Skin, Rectum, and Peripheral Blood in Allogeneic and Autologous Bone Marrow Transplant Recipients

Cited by 26 publications

References 0 publications

Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD

Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD

Rapid immunologic reconstitution following transplantation with mobilized peripheral blood stem cells as compared to bone marrow

Determination of helper T‐cell precursor frequencies against non‐haemopoietic cells: comparison of co‐stimulation provided by anti‐CD28 antibody versus the cellular ligand B7‐1

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