A Murine Model of Bone Marrow Failure Mediated by Disparity in Minor Histocompatibility Antigens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 132-132
Author(s):  
Jichun Chen ◽  
Neal S. Young

Abstract Destruction of hematopoietic cells in aplastic anemia and other hematologic diseases is mediated in most patients by effector cells of the immune system. We have developed a mouse model of immune-mediated bone marrow failure which employs parental lymph node cell infusion into F1 recipients, resulting in bone marrow hypercellularity, pancytopenia, and death from infection and bleeding, without other organ involvement by graft-versus-host disease (Bloom, ML et al. Exp. Hematol. 32:1163, 2004; Chen, J et al. Blood104:1671, 2004). Because major histocompatibility antigens are not the targets in acquired aplastic anemia, we now have developed a model of murine marrow failure based on disparity of minor histocompatibility antigens. Lymph node cells from C57BL/6 mice were infused into sublethally-irradiated, MHC-matched, C.B10-H2b/LilMce recipients. Animals developed severe pancytopenia and marrow hypoplasia within two-three weeks. CD8+ T lymphocytes were expanded in the blood and infiltrated bone marrow, becoming detectable at day 7 and reaching peak levels at days 10–12. There were no inflammatory responses observed in the skin, intestines, or other visceral organs by gross or microscopic pathological examination. In our experiments we observed a time-dependent expansion followed by contraction of CD8+ T cells specific for a minor histocompatibility antigen H60 as measured by flowcytometry using an H60-specific tetramer. H60 is an antigen peptide derived from a glycoprotein, a known ligand for stimulatory NKG2D receptors, and is immunodominant over other minor antigens in stem cell transplantation. The proportion of H60-specific CD8+ T cells was strongly negatively correlated with peripheral blood white cell, neutrophil, and platelet counts. Isolated H60-specific T-cells from bone marrow of affected animals induced apoptosis in vitro of normal C57BL/6 bone marrow cells in co-culture. The degree of apoptosis was further increased by addition of CD4 T-cells from same affected donors, suggesting a helper lymphocyte effect. The role of H60-specific T cells was demonstrated in further transplant experiments. Infusion of 5 × 106 C57BL/6 lymph node cells that had been depleted of H60-specific T cells was unable to induce marrow failure in C.B10 recipients, while the same number of cells with the addition of 20–90 × 103 H60-specific CD8+ T cells led to thrombocytopenia and leucopenia in recipients. H60-specific T cells thus appear to be key effectors, responsible at least for the initiation of marrow cell destruction. Mice could be treated with cyclosporine at 50 mg/g/day for five days, if treatments were begun at the time of lymph node cell infusion. Immunosuppressive therapy abolished H60-specific CD8+ T cell expansion and attenuated the development of peripheral pancytopenia, effectively rescuing animals. In conclusion, we demonstrate in this model of immune-mediated bone marrow failure that a single clone of peptide-specific T-cells is capable of efficient marrow destruction and the production of aplastic anemia.

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1202-1202
Author(s):  
Xingmin Feng ◽  
Zenghua Lin ◽  
Marie Desierto ◽  
Keyvan Keyvanfar ◽  
Daniela Malide ◽  
...  

Abstract Acquired aplastic anemia (AA) is bone marrow (BM) failure characterized by pancytopenia and marrow hypocellularity, in most patients due to immune attack by T cells that target hematopoietic stem and progenitor cells. Most patients respond to immunosuppressive therapy, but relapse, especially on withdrawal of cyclosporine A (CsA), occurs frequently (Scheinberg P, Am J Hematol., 2014). Rapamycin has been successful in some human autoimmune diseases and in mouse models of autoimmunity; rapamycin also appears to induce tolerance, as for example in the organ transplant setting. We have developed murine models of BM failure; animals can be salvaged by biologics and drugs that are effective in humans with AA. One purpose of these models is to test potential new therapies. We have compared rapamycin with customary immunosuppression by CsA. Infusion of lymph node cells from C57BL6 (B6) donor mice into CByB6F1 (F1) recipient mice (MHC-mismatched) induced massive BM destruction by activated T cells. Treatment with rapamycin (2 mg/kg/day, starting 1 hour post lymphocyte injection and continued for 2 weeks, n=9) effectively ameliorated pancytopenia and improved BM cellularity, better than did maximal dosing with CsA (50 mg/kg/day, starting 1 hour post lymphocyte injection, continued for 5 days, n=8) (Fig 1A). Rapamycin eliminated most BM-infiltrating CD8+ T cells, while CsA had less effect on CD8+ T cells than did rapamycin. Elimination of BM infiltrated T cells and restoration of megakaryocytes by rapamycin was visualized by confocal microscopy using whole-mounts of sternum, for which donor B6 lymph node cells were replaced with B6-DsRed lymph node cells. Plasma cytokines were measured by Luminex: IFNg, TNFa, IL-2, MIP1b, RANTES, sCD137 (all p < 0.001) were increased in BM failure mice compared with the control animals, indicating an inflammatory environment in AA. Rapamycin reduced these cytokines (p < 0.001) but increased Th2 cytokines such as IL-4 and IL-10 (p < 0.001) levels. CsA only decreased sCD137, reversely it even increased IFNg levels. Transcriptome analysis using pooled FACS-sorted CD4+ and CD8+ T cells from BM focusing on genes related to T cell functions revealed that rapamycin suppressed expression of Icam1, and Tnfsf14 in CD8+ T cells, and Cd27, Lgals3, Il10ra, Itga1, Tbx21, Gzmb, Tnfsf14 and Cd70 in CD4+ T cells, but increased Il-4, Il-2ra, and Tnfrsf8 expression in CD4+ T cells compared with AA mice. CsA suppressed Lgals3 in CD8+ T cells and Cd70 in CD4+ T cells, suggesting differential mechanisms of action by these two immunosuppressive drugs. All untreated AA mice (n=6) died within 3 weeks post lymphocyte infusion, while all mice treated with rapamycin for 2 weeks (n=8) survived until study termination at 7 weeks; similar results were obtained when we tested delayed treatment with rapamycin (starting 3 days post lymphocyte injection and continued for 10 days, n=8) in BM failure mice; but brief exposure to rapamycin, for only 5 days from 1 hour post lymphocyte infusion (n=8), could not rescue mice, suggesting a requirement for sustained administration. In contrast, all animals treated with CsA (n=6) died within 5 weeks (Fig 1B). We also tested the effect of rapamycin on antigen-specific T cells in another BM failure model induced by infusion of lymphocytes from B6 donor mice into C.B10-H2b /LilMcd recipient mice (MHC-matched but minor antigen-mismatched, n=10), in which BM destruction is mediated by H60-specific cytotoxic T cells (CTL) (Chen J, JI, 2007). Similar results were observed. Flow cytometry revealed massive expansion of H60-specific CTL in BM of untreated AA mice, rapamycin eliminated BM CD8+ T cell infiltration. CsA decreased BM CD8+ T cells, but had much weaker effect on H60 CTLs (Fig 1C). In summary, rapamycin is effective in treatment of AA murine models, which holds implications in the application in immune-mediated pathophysiologies in the laboratory and in the clinic. Compared with CsA, rapamycin suppressed expression of T cell activation genes more broadly, increased Th2 cytokines, eliminated antigen-specific T cells, and had better survival rate in animal BM failure model, supporting a clinical trial of rapamycin to prevent relapse and induce tolerance in patients with AA, many of whom are dependent on CsA administration for support of blood counts but at risk of CsA nephrotoxicity. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 180-180
Author(s):  
Gloria T Shan ◽  
Ivy Tran ◽  
Ashley R Sandy ◽  
Ann Friedman ◽  
Yi Zhang ◽  
...  

Abstract Abstract 180 Aplastic anemia is a severe bone marrow disorder characterized by the loss of hematopoietic stem cells (HSC). HSC destruction is thought to be T cell-mediated in a majority of patients with aplastic anemia. Global immunosuppression and HSC transplantation can induce disease remission, but these treatments are not effective in all patients and can promote life-threatening complications. Thus, novel immunomodulatory approaches are needed in this disorder. Notch is a conserved cell-cell communication pathway that can regulate T cell differentiation and function with context-dependent effects. To study the role of Notch signaling in pathogenic T cells causing immune-mediated bone marrow failure, we inhibited canonical Notch signaling in mature T cells through conditional expression of the pan-Notch inhibitor DNMAML (ROSA-DNMAMLf × Cd4-Cre mice). We used two complementary mouse models of immune-mediated bone marrow failure that mimic features of aplastic anemia: administration of C57BL/6 (B6) T cells into sublethally irradiated (500 rads) minor histocompatibility antigen mismatched BALB/b recipients (Chen et al., J Immunol 2007; 178:4159), or infusion of B6 lymphocytes into unirradiated MHC-mismatched B6×DBA F1 recipients. In contrast to control B6 T cells which led to lethal bone marrow failure in virtually all recipients, DNMAML-expressing Notch-deprived T cells were profoundly deficient at inducing HSC loss in both disease models, leading to markedly improved long-term survival (>90%). Notch-deficient T cells showed a modest decrease in overall expansion within secondary lymphoid organs, but their accumulation in the target bone marrow was preserved. Upon restimulation with anti-CD3 and anti-CD28 antibodies, DNMAML T cells had decreased production of IL-2 and interferon gamma. Activated CD4+ and CD8+ DNMAML T cells had reduced interferon gamma, granzyme B, and perforin transcripts despite preserved induction of the master transcription factors Tb×21 (encoding T-bet) and Eomes. In vivo infusion of CFSE-labeled host-type target cells revealed a decreased cytotoxicity in DNMAML as compared to control B6 T cell recipients. These observations point to a novel spectrum and mechanism of Notch action in mature T cells. Since we have shown recently that canonical Notch signaling is dispensable for the maintenance of adult HSCs (Maillard et al., Cell Stem Cell 2008, 2:356), our findings suggest that Notch inhibition could represent a novel therapeutic modality to target the T cell response and reverse immune-mediated HSC destruction in aplastic anemia. Disclosures: Shan: American Society of Hematology: Research Funding. Zhang:University of Michigan Comprehensive Cancer Center: Research Funding; Damon Runyon Cancer Research Foundation: Research Funding. Maillard:Damon Runyon Cancer Research Foundation: Research Funding; American Society of Hematology: Research Funding; University of Michigan Comprehensive Cancer Center: Research Funding.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2176-2176
Author(s):  
Xingmin Feng ◽  
Jisoo Kim ◽  
Gladys Gonzalez Matias ◽  
Zhijie Wu ◽  
Sabrina Solorzano ◽  
...  

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells with immunoregulatory function. Limited published studies have reported conflicting data concerning the effects of MDSCs on autoimmune diseases and graft-versus-host disease. MDSCs can be divided into two major subsets, more abundant granulocytic (G-MDSCs) and monocytic (M-MDSCs). We examined G-MDSCs in murine models of human bone marrow failure (BMF). We first characterized bone marrow (BM) MDSCs from C.B10 mice. CD11b +Ly6G +Ly6C low G-MDSCs suppressed in vitro proliferation of both CD4 and CD8 T cells from C57BL/6 (B6) mice, while Ly6G +Ly6C - cells had no effect and Ly6G -Ly6C + cells increased T cell proliferation (Fig. 1A). We then tested G-MDSCs in vivo utilizing antibody-mediated cell depletion. Lymph node (LN) cells from B6 donor mice were injected into sub-lethally irradiated major histocompatibility-mismatched CByB6F1 mice to induce BMF. Anti-Ly6G antibody injection worsened cytopenias and BM hypoplasia, and they increased BM CD4 and CD8 T cell infiltration. In contrast, anti-Ly6G antibody injection in the minor histocompatibility-mismatched C.B10 BMF model improved platelet counts and reduced BM CD8 T cells. The pathogenic and protective effects in the two models correlated with differential anti-Ly6G antibody modulation of G-MDSCs: in the CByB6F1 model, anti-Ly6G antibody eradicated G-MDSCs in blood and BM while in the C.B10 model the same antibody generated a novel G-MDSC cell population, of identical Ly6C lowCD11b + phenotype but intermediate Ly6G expression, which was not present in the CByB6F1 animals after antibody injection. When we examined the efficacy of G-MDSCs in C.B10 BMF: Ly6G + cells were enriched from BM of normal C.B10 donors (94%-97% Ly6C lowLy6G +CD11b +), and injected at the time of marrow failure initiation. Mice infused with Ly6G + cells had significantly higher levels of WBC, RBC, platelets, and total BM cells, decreased BM CD4 and CD8 T cell infiltration, and improved BM cellularity. These results indicated a protective role of G-MDSCs. When G-MDSCs were injected at day 3 after LN cell infusion, treated mice again had higher levels of WBC, RBC, platelets, and total BM cells at day 14, alleviating BMF. As both prophylaxis and therapy, G-MDSCs decreased Fas expression and Annexin V binding of residual BM cells, suppressed intracellular levels of gamma interferon and tumor necrosis factor alpha, as well as cell proliferation protein Ki67 levels in BM CD4 and CD8 T cells, relative to BMF control mice. TotalSeq simultaneously detecting surface proteins and mRNA expression in whole BM mononuclear cells in the therapy model showed an increased proportion of myeloid cells and reduced proportion of T cells in marrow from G-MDSC-treated mice based on cell surface markers and marker gene expression (Fig. 1B). Gene pathway analysis revealed down-regulation of Fas expression and reduced program cell death in total BM cells and decreased expression of genes related to cell cycle in infiltrating T cells from Ly6G + cell-treated mice-both results consistent with suppression by G-MDSCs of T cell proliferation and protection of target BM cells from apoptosis. In vitro culture of T cells from B6 mice with G-MDSCs which had been isolated from C.B10 BM cells showed dose-dependent suppression of T cell proliferation. In conclusion, our results demonstrate an active role of G-MDSCs in protecting BM from immune-mediated destruction, by suppression of T cell proliferation in the BM. G-MDSCs might have clinical application as treatment in human aplastic anemia and other immune-mediated and autoimmune diseases. Figure 1 Figure 1. Disclosures Young: Novartis: Research Funding.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1703-1703
Author(s):  
Bianca Serio ◽  
Ziad Peerwani ◽  
Ramon Tiu ◽  
Jennifer Powers ◽  
Erik Hsi ◽  
...  

Abstract Idiopathic aplastic anemia (AA) is characterized by immune-mediated destruction of hematopoietic stem cells, leading to peripheral pancytopenia. Immune pathogenesis in AA is supported by experimental data, as well as clinical observations and may be related to the breach of peripheral or central tolerance. Regulatory T cells (Treg) constitute one of the most important mechanisms of central tolerance engaged in the down-modulation of autoreactive T cells. Tregs have been found to be reduced in several autoimmune diseases and decreased frequencies of Tregs were also reported in AA and MDS. Overexpression of the high affinity IL-2 receptor alpha chain (CD25) and the forkhead family transcription factor P3 (FoxP3), required for the development and function of Tregs, serve as phenotypic markers for Tregs. We investigated Treg levels in a cohort of AA patients (N=21) and healthy individuals (N=15); flow cytometric quantification of Treg was carried out after surface/intracellular staining of whole blood for Treg markers (CD3, CD4, CD25, FoxP3). After proper gating (light scatter properties, CD3, CD4, CD25), CD4+ T cells were subdivided into CD25−, CD25int and CD25hi populations, and the co-expression of CD25hi and Foxp3 was analyzed. In comparison to controls, AA patients (N=12) show not only lower frequencies of CD4+CD25hi+ T cells within the total lymphocyte population (median 0.07% vs. 0.21%; p=.03), but also absolute lower absolute numbers (1.31/uL vs. 5.78/uL, p=.0002). Similarly, CD4+CD25hi+FoxP3+ T cells were found to be depressed in untreated AA patients in comparison to controls (median 0.07% vs. 0.21% and 1.06/uL vs. 4.76/uL; p=.03 and p=.003). While Tregs were lower in patients with active disease unresponsive to immunosuppressive treatment (responder 0.1% vs non responder 0.07%, CD4+CD25hi Tcells, p=.02), serial testing performed in 6 patients treated with ATG/CsA did not reveal correlation between hematologic improvement and recovery of Treg numbers. When double immunohistochemical staining for CD3 and Foxp3 was performed in pre-treatment bone marrow core biopsies of AA patients (N=3) and controls (N=2) a mean of 3 CD3+Foxp3+ cells/10 high power fields (hpf) were counted (vs. mean 28/10 hpf, p&lt;.05 in controls), suggesting that lower numbers of Tregs were also present in the bone marrow of AA patients. In conclusion, our results suggest that Tregs are decreased in blood and marrow of patients with idiopathic AA, consistent with the breach of peripheral tolerance in AA. In addition to flow cytometry, immunohistochemical staining of histologic specimens can be used for the quantitative analysis of Tregs in bone marrow failure syndromes and other immune-mediated conditions such as GvHD.


Author(s):  
Judith C.W. Marsh ◽  
Austin Kulasekararaj ◽  
Ghulam J. Mufti

Aplastic anaemia (AA) is a rare bone marrow failure (BMF) disorder characterized by pancytopenia and a hypocellular bone marrow. AA is commonly acquired, immune-mediated and idiopathic in nature. Activate auto-reactive, cytotxic CD8+ T-cells are present but recent work has shown that CD4+ T-cells appear to be more important in the pathogenesis of acquired AA. The immune nature of acquired AA provides the rationale for one of the treatment options, namely immunosuppressive therapy....


Blood ◽  
2018 ◽  
Vol 132 (26) ◽  
pp. 2730-2743 ◽  
Author(s):  
Wanling Sun ◽  
Zhijie Wu ◽  
Zenghua Lin ◽  
Maile Hollinger ◽  
Jichun Chen ◽  
...  

Abstract Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α−/− donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR−/− recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α−/− recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α−/− recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR−/− donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α–producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1037-1037
Author(s):  
Yong Tang ◽  
Jichun Chen ◽  
Neal Young

Abstract Patients with aplastic anemia have elevated T-bet, a Th1 transcription factor, in peripheral blood CD4 and CD8 T cells, suggesting that T-bet over-expression and dysregulated Th1 immune response contributes to pathophysiology of marrow failure (Solomou EE et al., Blood. 2006; 107:3983). In the present study, we studied the role of T-bet in inducing bone marrow failure in a mouse model of immune-mediated BM failure, employing mice engineered with a germline T-bet deletion as lymphocyte donors. Compared with T-bet +/+ wild-type controls, T-bet−/− mice have similar cellular composition in various lymphohematopietic tissues including peripheral blood, spleen, thymus, lymph nodes (LN), and BM. Incubation of effector T-bet−/− LN cells with MHC-mismatched target CByB6F1 (F1) BM cells in an in vitro cytotoxicity assay resulted in a significantly lower proportion of apoptotic target cells than did wild-type T-bet+/+ LN effector cells, suggesting that T-bet−/− effector LN cells are functionally defective. While infusion of 5×106 wild-type T-bet+/+ LN cells into sublethally-irradiated F1 mice led to severe pancytopenia and aplastic bone marrow in recipient mice, infusion of the same number of T-bet−/− LN cells failed to result in marrow failure, and recipients had relatively normal blood counts and bone marrow cellularity. By flow cytometry, both expansion of CD4+ and CD8+ T cells and elevation in intracellular Th1 cytokine gamma interferon (IFN-γ), which are characteristic of marrow cells in recipients received B6 LN cells, were absent in recipients receiving T-bet −/− LN cells. Serum IFN-γ concentration in F1 mice infused with T-bet −/− LN cells was similar to the level in F1 control mice received TBI alone, and both were significantly lower than serum IFN-γ in recipients of wild-type B6 LN cells. In contrast, serum TGF-γ concentration was higher in F1 mice that received TBI alone or TBI plus T-bet −/− LN cell infusion, compared with mice that received TBI plus B6 LN cells. An increase of T-bet −/− LN cell infusion to 10×106 cells per recipient led to very mild BM failure. Contrary to the markedly increased number of CD4+ and CD8+ T cells and elevated IFN-γ level in the BM of F1 mice which have received wild type B6 LN cells, F1 mice infused with T-bet −/− LN have low CD4+ and CD8+ cells and low IFN-γ level in the BM similar to F1 mice received TBI alone, but they show increased IL4 and IL17 levels within bone marrow T cells, indicating that the diminished Th1 immune response due to T-bet deficiency was partially compensated by up-regulated Th2 and Th17 responses. Our data demonstrated that T-bet plays a critical role in immune mediated bone marrow failure. Approaches targeting to T-bet signal pathway may lead to novel treatment for bone marrow failure and other autoimmune diseases.


2014 ◽  
pp. n/a-n/a ◽  
Author(s):  
Tao Zhang ◽  
Jianhong Wang ◽  
Xingchun Zhou ◽  
Rong Liang ◽  
Qingxian Bai ◽  
...  

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 541-548 ◽  
Author(s):  
Yong Tang ◽  
Marie J. Desierto ◽  
Jichun Chen ◽  
Neal S. Young

Abstract The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet−/−). In comparison with normal C57BL6 (B6) control mice, T-bet−/− mice had normal cellular composition in lymphohematopoietic tissues, but T-bet−/− lymphocytes were functionally defective. Infusion of 5 × 106 T-bet−/− lymph node (LN) cells into sublethally irradiated, major histocompatibility complex–mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet−/− LN-cell dose to 10 to 23 × 106 per recipient led to only mild hematopoietic deficiency. Recipients of T-bet−/− LN cells had no expansion in T cells or interferon-γ–producing T cells but showed a significant increase in Lin−Sca1+CD117+CD34− BM cells. Plasma transforming growth factor-β and interleukin-17 concentrations were increased in T-bet−/− LN-cell recipients, possibly a compensatory up-regulation of the Th17 immune response. Continuous infusion of interferon-γ resulted in hematopoietic suppression but did not cause T-bet−/− LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.


Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 553-556 ◽  
Author(s):  
FR Appelbaum ◽  
MA Cheever ◽  
A Fefer ◽  
R Storb ◽  
ED Thomas

Abstract Two patients with aplastic anemia were treated with high-dose cyclophosphamide and marrow transplantation from their normal, genetically identical twin. Both patients rapidly recovered normal marrow function, but marrow failure recurred 13 and 18 months later. Because donor and host pairs were identical twins, these cases of graft failure could not have resulted from the usual cause of graft failure, ie, immunological reactivity of host cells against unshared minor histocompatibility antigens of the donor. These results imply that there are at least two mechanisms responsible for graft failure after marrow transplantation for severe aplastic anemia.


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