Avaliação da Barreira Hemato-Encefálica no transplante de medula óssea

Almeida, Sérgio Monteiro de; Livramento, José Antonio; Pasqüini, Ricardo; Palou, Viviana Boccardi; Oliveira, Aparecido Mendes de; Doi, Elvira Missako; Ono, Margaret; Aso, Mirna Cigemi; Ferreira, Eurípides

doi:10.1590/S0004-282X1997000500019

Resumos

A barreira hemato-encefálica (BHE) contribui para o isolamento imunológico do sistema nervoso central (SNC). Sua avaliação nunca foi realizada em pacientes submetidos a transplante de medula óssea (TMO). Neste estudo a integridade da BHE foi avaliada através das proteínas do LCR, de forma quantitativa, a fim de observar a incidência e entender a fisiopatologia da doença do enxerto contra o hospedeiro crônica (DECH-C) no SNC. Foram estudadas amostras pareadas de LCR e soro de 33 pacientes com leucemia mielóide crônica submetidos a TMO alogênico, de doador aparentado, HLA idêntico. As amostras foram coletadas nos períodos pré TMO, pós TMO e concomitante à DECH-C. Não foi evidenciada quebra de BHE durante a DECH-C em nenhum dos casos estudados.

doença do enxerto contra o hospedeiro; barreira hemato-encefálica; auto-imunidade; líquido cefalorraquidiano; transplante de medula óssea; albumina

The blood-brain barrier (BBB) contributes to the central nervous system (CNS) immunological isolation. BBB has never been studied in patients who developed chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplants (BMT), from HLA identical related donors. BBB disruption was investigated through the cerebrospinal fluid (CSF) proteins, quantitative and graphically, in order to detect the incidence and possible pathophysiology of the CNS involvement in chronic GVHD. Thirty three CSF and matched serum samples from chronic myeloid leukemia patients were collected pre BMT, pos BMT and during chronic GVHD. There was no evidence of BBB disruption in any patient studied.

graft-versus-host disease; blood-brain barrier; auto immunity; cerebrospinal fluid; bone marrow transplantation; albumin

Avaliação da Barreira Hemato-Encefálica no transplante de medula óssea

Blood-Brain Barrier evaluation in bone marrow transplantation

Sérgio Monteiro de Almeida^I; José Antonio Livramento^I; Ricardo Pasqüini^II; Viviana Boccardi Palou^III; Aparecido Mendes de Oliveira^IV; Elvira Missako Doi^V; Margaret Ono^V; Mirna Cigemi Aso^V; Eurípides Ferreira^VI

^INeurologista

^IIProfessor Titular, Disciplina de Hematologia

^IIIBiologista

^IVBiomédico

^VBioquímica

^VIProfessor Adjunto, Disciplina de Imunologia

RESUMO

A barreira hemato-encefálica (BHE) contribui para o isolamento imunológico do sistema nervoso central (SNC). Sua avaliação nunca foi realizada em pacientes submetidos a transplante de medula óssea (TMO). Neste estudo a integridade da BHE foi avaliada através das proteínas do LCR, de forma quantitativa, a fim de observar a incidência e entender a fisiopatologia da doença do enxerto contra o hospedeiro crônica (DECH-C) no SNC. Foram estudadas amostras pareadas de LCR e soro de 33 pacientes com leucemia mielóide crônica submetidos a TMO alogênico, de doador aparentado, HLA idêntico. As amostras foram coletadas nos períodos pré TMO, pós TMO e concomitante à DECH-C. Não foi evidenciada quebra de BHE durante a DECH-C em nenhum dos casos estudados.

Palavras-chave: doença do enxerto contra o hospedeiro, barreira hemato-encefálica, auto-imunidade, líquido cefalorraquidiano, transplante de medula óssea, albumina.

ABSTRACT

The blood-brain barrier (BBB) contributes to the central nervous system (CNS) immunological isolation. BBB has never been studied in patients who developed chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplants (BMT), from HLA identical related donors. BBB disruption was investigated through the cerebrospinal fluid (CSF) proteins, quantitative and graphically, in order to detect the incidence and possible pathophysiology of the CNS involvement in chronic GVHD. Thirty three CSF and matched serum samples from chronic myeloid leukemia patients were collected pre BMT, pos BMT and during chronic GVHD. There was no evidence of BBB disruption in any patient studied.

Key words: graft-versus-host disease, blood-brain barrier, auto immunity, cerebrospinal fluid, bone marrow transplantation, albumin.

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Full text available only in PDF format.

Agradecimento - Ao Prof. Dr. Lineu César Werneck.

Aceite: 20-agosto-1997.

Projeto realizado com apoio da FAPESP (932705-6) e CAPES.

Estudo realizado na disciplina de Neurologia e Serviço de TMO do Hospital das Clínicas da Universidade Federal do Paraná (HC-UFPR), Disciplina de Imunologia da Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP) e Centro de Investigações em Neurologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP).

Dr. Sérgio Monteiro de Almeida - Especialidade de Neurologia, Hospital de Clínicas UFPR- Rua General Carneiro 181, sala 1238 - 80060-900 Curitiba PR - Brasil.

1. Almeida SM, Livramento JA, Pasqüini R, Palou VB, Oliveira AM, Doi EM, Ono M, Aso MC, Ferreira E. Avaliação da síntese intratecal de imunoglobulinas no transplante de medula óssea. Arq Neuropsiquiatr 1997;55:801-811.
2. Barker CF, Billingham RE. Immunologically privileged sites. Adv Immunol 1977;25:1-53.
3. Barrett J. Graft versus host disease. In:Treleaven J, Barrett J (eds). Bone marrow transplantation in practice. Edinburgh:Churchill Livingstone, 1992:257-272.
4. Bradbury MW. The concept of a blood brain barrier. London: John Wiley & Sons, 1979.
5. Breebart L, Becker H, Jongebloed FA. Investigation of reference values of components of CSF. J Clin Chem Clin Biochem 1978;16:561-565.
6. Deeg HJ, Henslee-Downey PJ. Management of acute graft-versus-host disease. Bone Marrow Transpl 1990;6:1-8.
7. Felgenhauer K, Schliep G, Rapic N. Evaluation of the blood-CSF barrier by protein gradients and the humoral immune response within the central nervous system. J Neurol Sci 1976;30:113-128.
8. Fishman RA. Cerebrospinal fluid in diseases of the nervous system. Ed2. London: W.B. Saunders, 1992.
9. Hauser SL, Bhan AK, Gilles FH, Hoban CJ, Reinherz EL, Schlossman SF, Weiner HL. Immunohistochemical of humam brain with monoclonal antibodies that identify lynphocytes, monocytes la antigens. J Neuroimmunol 1983;5:197-208.
10. Henry JB. Clinical and diagnosis management by laboratory methods. Ed18. Philadelphia: WB Saunders, 1991.
11. Hickey WF. Microglial participation in the initiation of CNS inflammation. Disc Neurose 1993;9:74-78.
12. Hickey WF, Kimura H. Graft vs. host disease elicits expression of class I and class II histocompatibility antigens and the presence of scattered T lymphocytes in rat central nervous system. Proc Natl Acad Sci USA 1987;84:2082-2086.
13. Iwasaki Y, Sako K, Ohara Y, Miyazawa M, Minegishi M, Tsuchiya S, Konno T. Subacute pan encephalitis associated with chronic graft-versus-host disease. Acta Neuropathol 1993;85:566-572.
14. Kajiwara K, Hirozane A, Fukumoto T, Orita T, Nishizaki T, Kamiryo T, Ito H. Major histocompatibility complex expression in brain of rats with graft-versus-host disease. J Neuroimmunol 1991;32:191-198.
15. Lampson LA, Hickey WF. Monoclonal antibody analysis of MHC expression in human brain biopsies:tissue ranging from histologically normal to that showing different levels of glial involvement. J Immunol 1986;136:4054-4062.
16. Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. II.Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest 1977;37:391-396.
17. Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 1965;2:235-254.
18. Marosi C, Budka H, Grimm G, Zeitlhofer J, Sluga E, Brunner C, Schneeweiss B, Vole B, Bettelheim P, Panzer S, Kier P, Graninger W, Haas OA, Hinterberger W. Fatal encephalitis in a patient with chronic graft-versus-host disease. Bone Marrow Transpl 1990;6:53-57.
19. Mathe G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Haematopoietic chimera in man after allogenic (homologous) bone-marrow transplantationxontrol of the secondary syndrome. Specific tolerance due to the chimerism. Br Med J 1963;28:1633-1635.
20. Matsumoto Y, Fujiwara M. In situ detection of class I and class II major histocompatibility antigens in the rat central nervous system during experimental allergic encephalomyelitis: an immunohistochemical study. J Neroimmunol 1986;12:265-277.
21. Matsumoto Y, Hara N, Tanaka R, Fujiwara M. Immunohistochemical analysis of the rat central nervous system during experimental allergic encephalomyelitis, with special reference to la-positive cells with dentritic morphology. J Immunol 1986;136:3668-3676.
22. Meulemans O. Determination of total protein in spinal fluid with sulphosalicylic acid and trichloro-acetic acid. Clin Chim Acta 1960;5:757-761.
23. Openshaw H, Slatkin NE. Neurological complications of bone marrow transplantation. In:Forman SJ, Blume KG, Thomas ED (eds). Bone marrow transplantation. Boston: Blackwell, 1994: .482-496.
24. Pardridge WM. The blood-brain barriencellular and molecular biology. New York:Raven Press, 1993.
25. Parkman R. Clonal analysis of murine graft-vs-host disease:I.Phenotypic and functional analysis of T lymphocyte clones. J Immunol 1986;136 :3543-3547.
26. Parkman R. Graft-versus-host disease and cytokines. Cur Op Hematol 1993:223-237.
27. Patchell R A, White HI CL, Clark AW, Beschorner WE, Santos GW. Neurologic complications of bone marrow transplantation. Neurology 1985;35:300-306.
28. Rouan E, Gruber R, Shearer W, Armstrong D, Hawkins EP. Graft-versus-host disease in central nervous system:a real emity? Am J Clin Pathol 1988;89:543-546.
29. Santos GW. History of bone marrow transplantation. Clin Haematol 1983;12:611-639.
30. Santos GW, Cole LJ. Effects of donor and host lymphoid and myeloid tissue injections in lethally X-irradiated mice treated with rat bone marrow. J Nat Cancer Inst 1958;21:279-293.
31. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi M, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-217.
32. Schliep G, Felgenhauer K. Serum-CSF protein gradients, the blood-CSF barrier and local immune response. J Neurol 1978;218:77-96.
33. Sobel RA, Ames MB. Major histocompatibility complex molecule expression in the human central nervous system:immunohistochemical analysis of 40 patients. J Neuropathol Exp Neurol 1988;47:19-28.
34. Thompson, EJ. The CSF Proteins:a biochemical approach. Amsterdam:Elsevier, 1988.
35. Tibbling G, Link H, Ohman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-390.
36. Traugott U, Scheinberg LC, Raine CS. On the presence of la-positive endothelial cells and astrocytes in multiple sclerosis lesions and its revelance to antigen presentation. J Neuroimmunol 1985;8:1-14.
37. Van Bekkum DW. What is graft versus host disease? Bone Marrow Transpl 1991;7(Suppl 2):110-111.
38. Wiznitzer M, Packer RJ, August CS, Burkey ED. Neurological complications of bone marrow transplantation in childhood. Ann Neurol 1984;16:569-576.
39. Woodroofe MN, Bellamy AS, Feldman M, Davison AN, Cuzner ML. Immunocytochemical characterisation of imune reaction in the central nervous system in multiple sclerosis:possible role for microglia in lesion growth. J Neurol Sci 1986;74:135-152.

Datas de Publicação

Publicação nesta coleção
21 Out 2010
Data do Fascículo
1997

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Almeida SM, Livramento JA, Pasqüini R, Palou VB, Oliveira AM, Doi EM, Ono M, Aso MC, Ferreira E. Avaliação da síntese intratecal de imunoglobulinas no transplante de medula óssea. Arq Neuropsiquiatr 1997;55:801-811.

[2] 2. Barker CF, Billingham RE. Immunologically privileged sites. Adv Immunol 1977;25:1-53.

[3] 3. Barrett J. Graft versus host disease. In:Treleaven J, Barrett J (eds). Bone marrow transplantation in practice. Edinburgh:Churchill Livingstone, 1992:257-272.

[4] 4. Bradbury MW. The concept of a blood brain barrier. London: John Wiley & Sons, 1979.

[5] 5. Breebart L, Becker H, Jongebloed FA. Investigation of reference values of components of CSF. J Clin Chem Clin Biochem 1978;16:561-565.

[6] 6. Deeg HJ, Henslee-Downey PJ. Management of acute graft-versus-host disease. Bone Marrow Transpl 1990;6:1-8.

[7] 7. Felgenhauer K, Schliep G, Rapic N. Evaluation of the blood-CSF barrier by protein gradients and the humoral immune response within the central nervous system. J Neurol Sci 1976;30:113-128.

[8] 8. Fishman RA. Cerebrospinal fluid in diseases of the nervous system. Ed2. London: W.B. Saunders, 1992.

[9] 9. Hauser SL, Bhan AK, Gilles FH, Hoban CJ, Reinherz EL, Schlossman SF, Weiner HL. Immunohistochemical of humam brain with monoclonal antibodies that identify lynphocytes, monocytes la antigens. J Neuroimmunol 1983;5:197-208.

[10] 10. Henry JB. Clinical and diagnosis management by laboratory methods. Ed18. Philadelphia: WB Saunders, 1991.

[11] 11. Hickey WF. Microglial participation in the initiation of CNS inflammation. Disc Neurose 1993;9:74-78.

[12] 12. Hickey WF, Kimura H. Graft vs. host disease elicits expression of class I and class II histocompatibility antigens and the presence of scattered T lymphocytes in rat central nervous system. Proc Natl Acad Sci USA 1987;84:2082-2086.

[13] 13. Iwasaki Y, Sako K, Ohara Y, Miyazawa M, Minegishi M, Tsuchiya S, Konno T. Subacute pan encephalitis associated with chronic graft-versus-host disease. Acta Neuropathol 1993;85:566-572.

[14] 14. Kajiwara K, Hirozane A, Fukumoto T, Orita T, Nishizaki T, Kamiryo T, Ito H. Major histocompatibility complex expression in brain of rats with graft-versus-host disease. J Neuroimmunol 1991;32:191-198.

[15] 15. Lampson LA, Hickey WF. Monoclonal antibody analysis of MHC expression in human brain biopsies:tissue ranging from histologically normal to that showing different levels of glial involvement. J Immunol 1986;136:4054-4062.

[16] 16. Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. II.Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest 1977;37:391-396.

[17] 17. Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 1965;2:235-254.

[18] 18. Marosi C, Budka H, Grimm G, Zeitlhofer J, Sluga E, Brunner C, Schneeweiss B, Vole B, Bettelheim P, Panzer S, Kier P, Graninger W, Haas OA, Hinterberger W. Fatal encephalitis in a patient with chronic graft-versus-host disease. Bone Marrow Transpl 1990;6:53-57.

[19] 19. Mathe G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Haematopoietic chimera in man after allogenic (homologous) bone-marrow transplantationxontrol of the secondary syndrome. Specific tolerance due to the chimerism. Br Med J 1963;28:1633-1635.

[20] 20. Matsumoto Y, Fujiwara M. In situ detection of class I and class II major histocompatibility antigens in the rat central nervous system during experimental allergic encephalomyelitis: an immunohistochemical study. J Neroimmunol 1986;12:265-277.

[21] 21. Matsumoto Y, Hara N, Tanaka R, Fujiwara M. Immunohistochemical analysis of the rat central nervous system during experimental allergic encephalomyelitis, with special reference to la-positive cells with dentritic morphology. J Immunol 1986;136:3668-3676.

[22] 22. Meulemans O. Determination of total protein in spinal fluid with sulphosalicylic acid and trichloro-acetic acid. Clin Chim Acta 1960;5:757-761.

[23] 23. Openshaw H, Slatkin NE. Neurological complications of bone marrow transplantation. In:Forman SJ, Blume KG, Thomas ED (eds). Bone marrow transplantation. Boston: Blackwell, 1994: .482-496.

[24] 24. Pardridge WM. The blood-brain barriencellular and molecular biology. New York:Raven Press, 1993.

[25] 25. Parkman R. Clonal analysis of murine graft-vs-host disease:I.Phenotypic and functional analysis of T lymphocyte clones. J Immunol 1986;136 :3543-3547.

[26] 26. Parkman R. Graft-versus-host disease and cytokines. Cur Op Hematol 1993:223-237.

[27] 27. Patchell R A, White HI CL, Clark AW, Beschorner WE, Santos GW. Neurologic complications of bone marrow transplantation. Neurology 1985;35:300-306.

[28] 28. Rouan E, Gruber R, Shearer W, Armstrong D, Hawkins EP. Graft-versus-host disease in central nervous system:a real emity? Am J Clin Pathol 1988;89:543-546.

[29] 29. Santos GW. History of bone marrow transplantation. Clin Haematol 1983;12:611-639.

[30] 30. Santos GW, Cole LJ. Effects of donor and host lymphoid and myeloid tissue injections in lethally X-irradiated mice treated with rat bone marrow. J Nat Cancer Inst 1958;21:279-293.

[31] 31. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi M, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-217.

[32] 32. Schliep G, Felgenhauer K. Serum-CSF protein gradients, the blood-CSF barrier and local immune response. J Neurol 1978;218:77-96.

[33] 33. Sobel RA, Ames MB. Major histocompatibility complex molecule expression in the human central nervous system:immunohistochemical analysis of 40 patients. J Neuropathol Exp Neurol 1988;47:19-28.

[34] 34. Thompson, EJ. The CSF Proteins:a biochemical approach. Amsterdam:Elsevier, 1988.

[35] 35. Tibbling G, Link H, Ohman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-390.

[36] 36. Traugott U, Scheinberg LC, Raine CS. On the presence of la-positive endothelial cells and astrocytes in multiple sclerosis lesions and its revelance to antigen presentation. J Neuroimmunol 1985;8:1-14.

[37] 37. Van Bekkum DW. What is graft versus host disease? Bone Marrow Transpl 1991;7(Suppl 2):110-111.

[38] 38. Wiznitzer M, Packer RJ, August CS, Burkey ED. Neurological complications of bone marrow transplantation in childhood. Ann Neurol 1984;16:569-576.

[39] 39. Woodroofe MN, Bellamy AS, Feldman M, Davison AN, Cuzner ML. Immunocytochemical characterisation of imune reaction in the central nervous system in multiple sclerosis:possible role for microglia in lesion growth. J Neurol Sci 1986;74:135-152.