Abstract
Immune-mediated stem cell damage has been postulated to be responsible for disease initiation and progression in aplastic anemia (AA). It is hypothesized that T lymphocytes play a major role in destroying the bone marrow (BM) stem cells of AA patients by infiltrating the BM and secreting excessive levels of anti-hematopoietic cytokines, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). We undertook this study to assess the pathogenic significance of anti-hematopoietic cytokines such as IFN-γ and TNF-α in BM T cells and plasma of AA patients. Significantly elevated levels of IFN-γ and TNF-α were found in the BM plasma of AA patients compared to controls (p=0.05 and 0.006, respectively). Intracellular IFN-γ and not TNF-α in BM CD3+ T cells of AA patients was significantly higher compared to controls (p=0.04 and p=0.2, respectively). A follow-up analysis of expression of these cytokines in BM T cells and their levels in BM plasma in five AA patients before and 180 days (6 months) after antithymocyte globulin (ATG) and cyclosporin A (CsA) therapy showed a decline 180 days after therapy compared to pre-therapy. We thus conclude that increased production of both IFN-γ and TNF-α in the BM may contribute to disease pathogenesis in AA and ATG therapy may induce hematological remission by suppressing the elevated levels of IFN-γ and TNF-α in AA BM.
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Bacigalupo A, How J, Gluckman E, Nissen C, Marsh J, Van Lint MT (1988) Bone marrow transplantation (BMT) versus immunosuppression for treatment of severe aplastic anaemia (SAA): a report of EBMT SAA working party. Br J Haematol 70:177–182
Camitta BM, Rappenport JM, Parkmann R, Nathan DG (1975) Selection of patients for bone marrow transplantation in severe aplastic anemia. Blood 45:355–363
Dubey S, Srivastava A, Nityanand S (2002) Induction of apoptosis of peripheral blood mononuclear cells by antithymocyte globulin (ATG) in aplastic anemia: an in vivo and in vitro study. Ann Hematol 81:249–253
Dufour C, Corcione A, Svahn J, Haupt R, Battillana N, Pistola V (2001) Interferon-γ and tumour necrosis factor-α are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anaemia. Br J Haematol 115:1023–1031
Frickhoven N, Rosenfeld SJ (2000) Immunosuppressive treatment of aplastic anemia with antilymphocyte globulin and cyclosporine. Semin Hematol 37:56–68
Hinterberger W, Gunther A, Gerald A, Dudczak R, Geibler K, Hocker P, Huber C, Kalhs P, Knapp W, Koller U, Lechner K, Platzer B (1988) Further evidence for lymphokine overproduction in aplastic anemia. Blood 72:266–272
Martinez-Jaramillo MG, Figueroa EF, Morales GG, Valle ES, Mayani H (2001) Tumor necrosis factor-alpha levels in long-term marrow cultures from patients with aplastic anemia: modulation by granulocyte–macrophage colony-stimulating factor. Am J Hematol 68:144–148
Jung T, Schauer U, Heusser C, Neumann C, Rieger C (1993) Detection of intracellular cytokines by flow cytometry. J Immunol Methods 159:197–207
Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS (1995) Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anemia. Br J Haematol 91:245–252
Maciejewski JP, Anderson S, Katevas P, Young NS (1994) Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. Br J Haematol 87:227–234
Melenhorst JJ, Van Krieken J, Dreef E, Landegent JE, Willemze R, Fibbe WE (1997) T cell selectively infiltrates bone marrow areas with residual hematopoiesis of patients with acquired anemia. Br J Haematol 99:517–519
Risitano AM, Kook H, Zeng W, Chen G, Young NS, Maciejewski JP (2002) Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by V beta CDR3 spectratyping and flow cytometry. Blood 100:178–183
Risitano AM, Maciejewski JP, Green S, Plasilova M, Zeng W, Young NS (2004) In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet 364:355–364
Schultz JC, Shahidi NS (1994) Detection of tumor necrosis factor-α in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia. Am J Hematol 45:32–38
Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP (1995) Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol 165:538–546
Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS (2002) Intracellular interferon-γ in circulating and marrow T cells detected by flow cytometry and response to immunosuppressive therapy in patients with aplastic anemia. Blood 100:1185–1191
Young NS (2002) Acquired aplastic anemia. Ann Med 136:534–546
Young NS, Barret JA (1995) The treatment of severe acquired aplastic anemia. Blood 85:3367–3377
Young NS (2000) Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia. Semin Hematol 37:3–14
Zeng W, Nakao S, Takamatsu H, Yachie A, Takami A, Kondo Y, Sugimori N, Yamazaki H, Miura Y, Shiobara S, Matsuda T (1999) Characterization of T-cell repertoire of the bone marrow in immune-mediated aplastic anemia: evidence for the involvement of antigen-driven T-cell response in cyclosporine-dependent aplastic anemia. Blood 93:3008–3016
Zoumbos NC, Gascon P, Djeu J, Trost SR, Young NS (1985) Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med 312:257–264
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Dubey, S., Shukla, P. & Nityanand, S. Expression of interferon-γ and tumor necrosis factor-α in bone marrow T cells and their levels in bone marrow plasma in patients with aplastic anemia. Ann Hematol 84, 572–577 (2005). https://doi.org/10.1007/s00277-005-1022-8
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DOI: https://doi.org/10.1007/s00277-005-1022-8