- Email: [email protected]
Childhood immune thrombocytopenic purpura
ITP in childhood
Childhood immune thrombocytopenic purpura D. J. Nugent Division of Hematology, Hemostasis / Thrombosis Research, Children’s Hospital of Orange County, Orange, CA
Abstract Childhood immune thrombocytopenic purpura (ITP) is acute and generally seasonal in nature, suggesting that infectious or environmental agents may trigger the immune response to produce platelet-reactive autoantibodies 4 to 8 weeks following an infection. In general, the patient is well apart from the diffuse bruising and petechiae indicative of a profound thrombocytopenia. Over a period of 6 months, the thrombocytopenia resolves in approximately 85% of children, while the remaining 15% with persistent platelet consumption are designated as chronic ITP patients. The peak age of acute ITP is 2 to 5 years of age, a period when children experience the greatest frequency of viral infections. Children with the chronic form of ITP mirror the adult phenotype, in that females predominate, and there is no seasonal fluctuation of the disease. Evidence from our laboratory suggests that the activated platelet itself may play a role in perpetuating autoantibody production and immune dysregulation associated with ITP. Current data on lymphocyte studies and cytokine alterations noted in response to the variety of regimens used in children with ITP suggest that acute ITP is accompanied by autoantibodies to GPIb and a cytokine profile that is proinflammatory in nature. Early recognition of the immune dysregulation driving acute versus chronic ITP will distinguish those children who might benefit from immunotherapy versus those who will recover without therapeutic intervention. ° C 2002, Elsevier Science Ltd. All rights reserved.
INTRODUCTION mmune thrombocytopenic purpura (ITP) is one of the most common forms of autoimmune disease in children. Acute ITP occurs in 90% of the children who sooner or later spontaneously recover. Prospective studies indicate that childhood ITP occurs with the same frequency in males as in females. It is generally seen in children from the ages of 1 to 9 years, though the peak manifestation is between 2 to 5 years of age. It has a seasonal presentation and is often seen more in winter and fall. The most common form of childhood ITP seen by physicians is a healthy child covered with bruises. The child is well, does not have a fever, but has considerable bruises and petechiae indicative of a profound thrombocytopenia. Patient history will indicate the occurrence of a previous illness, allergies, immunizations, or a viral illness in the family. Indeed, platelet-specific autoantibodies are generally observed 4 to 8 weeks following a viral illness or exposure. The onset of thrombocytopenia is very rapid and is distinctly different from chronic, adult thrombocytopenia. It is also different from the thrombocytopenia associated with varicella zoster infections
I
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
where the thrombocytopenia occurs concurrent with or immediately following the illness.
MECHANISM OF CHILDHOOD ITP Antibodies in the idiotypic network are comprised of lowaffinity molecules that have cross-reactivity with viral and other antigens. It is thought that the idiotypic network mimics not only the environment we live in, but also the bacteria and viruses we might be exposed to, a phenomenon known as molecular mimicry. Thus, when contact to viral and bacterial antigens occurs, high-affinity antibodies with broad specificity are generated, as demonstrated by experiments in syngeneic mice.1,2 In addition, the education process of the idiotypic network begun in utero by maternal IgG is not complete in humans until the age of 4 or 5 years, and this education can go awry in the early years with viral infections, generating cross-reactive autoantibodies. In the mature individual, crossreactive autoantibodies are suppressed, but in the younger child whose idiotypic network is still forming, there is a higher likelihood of their expression following infection, immunization or other environmental triggers. It is generally held that the production of autoantibodies is driven and controlled by cellular and soluble regulatory mechanisms. Peripheral control of self-tolerance, for example, prevents the emergence of pathologic antibodies. Immune changes that may affect these mechanisms occur in pregnancy, HIV infections, lupus, and other autoimmune diseases, and may be responsible for the development of thrombocytopenia. In all such cases of immune dysregulation, it is not uncommon to see antiplatelet antibody production. There is good evidence for the involvement of T cells in autoimmune diseases, but the T cells responsible for loss of self-tolerance in children with ITP are more difficult to isolate than the platelet autoantibodies. The specific T cells that trigger the disease and their initial target antigens are difficult to identify due to a phenomenon called epitope spreading. At the onset, the T-cell response may be directed against a specific, infectious antigenic epitope, but over time the T cells expand and diversify. New T-cell clones emerge that react with other parts of the same protein or with other molecules in the damaged or activated platelet, stimulating the production of autoreactive B cells previously tolerant to these epitopes.3–5
CYTOKINE PROFILE The cytokine profile in an individual is important in immune regulation, in particular for the primordial T helper lymphocyte precursor, Th0 cell, to differentiate into the Th1 (proinflammatory) or Th2 (down regulator) subsets.6,7 Patients with acute ITP have low levels of interleukin (IL)-4 and IL-6, a profile that is similar to that in children with acute onset of diabetes and arthritis.8 IL-4 is noted for turning off the proinflammatory response, commonly associated with a Th2 response. Hence, in its absence, T cells are frozen in the Th1 or proinflammatory mode. In children, low levels of IL-4 and IL-6 are responsible for the increased expression of HLA-DR Class II molecules on platelet surfaces, a situation very similar to adult, chronic ITP. Additionally, young platelets also c °
2002, Elsevier Science Ltd. All rights reserved.
Blood Reviews (2002) 16, 27–29
doi: 10.1054/blre.2001.0177, available online at http://www.idealibrary.com on
27
Nugent express other immunogenic molecules important in antigen presentation. The plasma cell, an immunoglobulin-producing B cell, is physiologically present in very small numbers. The majority of B cells are in the presecretory state, in which, they are excellent antigen-presenting cells. Unlike macrophages that process large portions of cellular material, the B cell does a more efficient job of antigen presentation than macrophages or dendritic cells.9 Via their surface immunoglobulin molecules, B cells can process antigens and present the peptides in context of the MHC molecules on their surface to T cells. This interaction between T and B cells induces resting B cells to proliferate and produce immunoglobulin, whether it is in response to viruses, or naturally occurring autoantibodies directed against aging platelets or other senescent hematopoietic cells.
PLATELETS AS T CELLS A current concept that is being tested in our laboratory is the premise that platelets can act as sham T cells. In their activated state, platelets express CD40L and CD69. In proximity to B cells, the platelets are able to interact with antigens on B-cell surfaces in the context of the immunoglobulin receptor or MHC molecules, producing cytokines such as IL-1. The proinflammatory effect of IL-1 is B-cell proliferation. Thus, platelet antigens may be involved in the stimulation of B cells to produce platelet autoantibodies. Because IL-1 drives the proinflammatory response by suppressing IL-4 production, we tried to determine the effect of platelets in the phytohemagglutinin stimulation of a mixed population of monocytes and in the production of IL-1. When platelets are added to PHA stimulated mononuclear cells there is a significant increase in IL-1 production particularly in the B cell and monocyteenriched fractions. Platelets did not increase the production of γ interferon in the same PHA-stimulated cultures.12 Following viral infections, platelets, by increasing IL-1 production, can be viewed as stimulating autoantibody production. Antigen specificity may determine whether the ITP is chronic or acute, depending on the maturity and effectiveness of the T lymphocyte suppressors and anti-idiotypic antibodies.13 These studies will begin to distinguish the normal versus pathologic responses to environmental triggers in ITP.
THERAPY FOR CHILDHOOD ITP The management of childhood ITP is controversial. Most practices are based on an empiric approach rather than guided by relevant clinical data. Bone marrow aspiration is only indicated if a diagnosis of persistent thrombocytopenia is established or if patients are unresponsive to intravenous immunoglobulin (IVIg). Treatment options are better defined after assessing the risk of hemorrhage. Thus, it is important to differentiate between a simple hemorrhagic purpura of the skin and mucous membrane bleeding. The indication to treat children with acute ITP should depend on clinical signs, symptoms, and quality-of-life issues. An important rationale to treat children is the unpredictable event of intracranial hemorrhage. The event is very rare, and thus there may be value in treating 28
Blood Reviews (2002) 16, 27–29
c °
2002, Elsevier Science Ltd. All rights reserved.
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
only those children exhibiting severe thrombocytopenia or active bleeding regardless of platelet count. Treatment options include IVIg, corticosteroids, anti-D (if the patient is Rh(D)-positive), platelet transfusion for uncontrolled bleeding, and splenectomy. Because up to 70% of the children recover even from severe thrombocytopenia without specific treatment and register platelet counts of 50,000/µL to 100,000/µL within 3 months,14–18 there is an argument to be made for no treatment. The indication for hospitalization should be reserved for cases where the clinical situation demands for such an approach, such as life-threatening bleeding, and the patient should be treated with IVIg, intravenous methylprednisolone, and platelet transfusion. If the patient’s platelet count is <20,000 / µL with mucous membrane bleeding (wet hemorrhage), the patient should be hospitalized and treated with either IVIg, intravenous corticosteroids, oral corticosteroids, or anti-D. With the same platelet count accompanied by mild bleeding (dry hemorrhage) or no bleeding, hospitalization of the patient is optional, and either no treatment or the same treatment as for mucous membrane bleeding is appropriate. If the child is asymptomatic and has a platelet count <20,000 / µL, observation alone may be warranted.19 The excellent response of thrombocytopenic patients to the infusion of high-dose IVIg, anti-D, or antibody to lymphocyte accessory molecules provides strong evidence that immunomodulatory therapy is feasible in ITP. Most physicians concur that Fc-blockade plays a major role in the success of IVIg and anti-D infusions, which induce a rise in platelet count in the majority of patients regardless of age or etiology of ITP. Apart from reducing splenic clearance of platelets, there is evidence that treatment also alters T-cell subsets, interferes with the production of pathologic antibodies, and may produce alterations in cytokine production.
Correspondence to: Diane J. Nugent , MD, Division of Hematology, Hemostasis / Thrombosis Research, Children’s Hospital of Orange County, 455 South Main Street, Orange, CA 92868. E-mail: [email protected]
References 1. Andrade L, Martinez-AC, Coutinho C. Mother-derived selection of immune repertoires: nongenetic transmission of developmental choices. G. Chaouat, ed. The Immunology of the Fetus 187. CRC Press, Boca Raton, FL, 1990. 2. Lemke H, Lange H, Berek C. Maternal immunization modulates the primary immune response to 2-phenyl-oxazolone in BALB/c mice. Eur J Immunol 1994; 24: 3025–3030. 3. Ware RE, Howard TA. Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura. Blood 1993; 82: 2137–2142. 4. Mamula MJ. Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes. Immunol Rev 1998; 164: 231–239. 5. Farris AD, Keech CL, Gordon TP, McCluskey J. Epitope mimics and determinant spreading: pathways to autoimmunity. Cell Mol Life Sci 2000; 57: 569–578.
ITP in childhood 6. Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, Freedman J. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood 1996; 87: 4245 – 4254. 7. Shevack E. Organ-specific autoimmunity, in Paul WE (ed): Fundamental Immunology. 4th ed. Philadelphia, PA, Lippincott-Raven Publishers, 1999; pp 1089–1125. 8. Nugent D, Berman M, Imfeld K, Dadufalza V, Sandborg C. Depressed IL-4 levels in children with acute and chronic immune thrombocytopenia (ITP). FASEB 1998; 12: A609 (abstr). 9. Liang B, Mamula MJ. Molecular mimicry and the role of B lymphocytes in the processing of autoantigens. Cell Mol Life Sci 2000; 57: 561–568. 10. Ziegler SF, Ramsdell F, Alderson MR. The activation antigen CD69. Stem Cells 1994; 12: 456 – 465. 11. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591–594.
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .
12. Nugent D, Imfeld K, Berman M. Cytokine stimulation by platelets and GPIb immunodominant peptides. Thrombo Haemost 2001; 86: 995 (abstr). 13. Semple JW. Immunobiology of T helper cells and antigen-presenting cells in autoimmune thrombocytopenic purpura (ITP). Acta Paediatr Suppl 1998; 424: 41– 45. 14. Lusher JM, Iyer R. Idiopathic thrombocytopenic purpura in children. Semin Thrombo Hemost 1977; 3: 175–199. 15. Lusher JM, Enami A, Ravindranath V, Warrier AI. Idiopathic thrombocytopenic purpura in children. Am J Pediatr Hematol Oncol 1984; 6: 149–157. 16. Walker RW, Walker W. Idiopathic thrombocytopenic purpura, initial illness and long term follow up. Arch Dis Child 1984; 59: 316–322. 17. Medeiros D, Buchanan GR. Major hemorrhage in children with idiopathic thrombocytopenic purpura: immediate response to therapy and long-term outcome. J Pediatr 1998; 133: 334 – 339. 18. Medeiros D, Buchanan GR. Idiopathic thrombocytopenic purpura: beyond consensus. Curr Opin Pediatr 2000; 12: 4 – 9. 19. Kuhne T, Imbach P. Management of children with acute and chronic immune thrombocytopenic purpura. Transfus Sci 1998; 19: 261–268.
c °
2002, Elsevier Science Ltd. All rights reserved.
Blood Reviews (2002) 16, 27–29
29
Childhood immune thrombocytopenic purpura D. J. Nugent Division of Hematology, Hemostasis / Thrombosis Research, Children’s Hospital of Orange County, Orange, CA
Abstract Childhood immune thrombocytopenic purpura (ITP) is acute and generally seasonal in nature, suggesting that infectious or environmental agents may trigger the immune response to produce platelet-reactive autoantibodies 4 to 8 weeks following an infection. In general, the patient is well apart from the diffuse bruising and petechiae indicative of a profound thrombocytopenia. Over a period of 6 months, the thrombocytopenia resolves in approximately 85% of children, while the remaining 15% with persistent platelet consumption are designated as chronic ITP patients. The peak age of acute ITP is 2 to 5 years of age, a period when children experience the greatest frequency of viral infections. Children with the chronic form of ITP mirror the adult phenotype, in that females predominate, and there is no seasonal fluctuation of the disease. Evidence from our laboratory suggests that the activated platelet itself may play a role in perpetuating autoantibody production and immune dysregulation associated with ITP. Current data on lymphocyte studies and cytokine alterations noted in response to the variety of regimens used in children with ITP suggest that acute ITP is accompanied by autoantibodies to GPIb and a cytokine profile that is proinflammatory in nature. Early recognition of the immune dysregulation driving acute versus chronic ITP will distinguish those children who might benefit from immunotherapy versus those who will recover without therapeutic intervention. ° C 2002, Elsevier Science Ltd. All rights reserved.
INTRODUCTION mmune thrombocytopenic purpura (ITP) is one of the most common forms of autoimmune disease in children. Acute ITP occurs in 90% of the children who sooner or later spontaneously recover. Prospective studies indicate that childhood ITP occurs with the same frequency in males as in females. It is generally seen in children from the ages of 1 to 9 years, though the peak manifestation is between 2 to 5 years of age. It has a seasonal presentation and is often seen more in winter and fall. The most common form of childhood ITP seen by physicians is a healthy child covered with bruises. The child is well, does not have a fever, but has considerable bruises and petechiae indicative of a profound thrombocytopenia. Patient history will indicate the occurrence of a previous illness, allergies, immunizations, or a viral illness in the family. Indeed, platelet-specific autoantibodies are generally observed 4 to 8 weeks following a viral illness or exposure. The onset of thrombocytopenia is very rapid and is distinctly different from chronic, adult thrombocytopenia. It is also different from the thrombocytopenia associated with varicella zoster infections
I
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
where the thrombocytopenia occurs concurrent with or immediately following the illness.
MECHANISM OF CHILDHOOD ITP Antibodies in the idiotypic network are comprised of lowaffinity molecules that have cross-reactivity with viral and other antigens. It is thought that the idiotypic network mimics not only the environment we live in, but also the bacteria and viruses we might be exposed to, a phenomenon known as molecular mimicry. Thus, when contact to viral and bacterial antigens occurs, high-affinity antibodies with broad specificity are generated, as demonstrated by experiments in syngeneic mice.1,2 In addition, the education process of the idiotypic network begun in utero by maternal IgG is not complete in humans until the age of 4 or 5 years, and this education can go awry in the early years with viral infections, generating cross-reactive autoantibodies. In the mature individual, crossreactive autoantibodies are suppressed, but in the younger child whose idiotypic network is still forming, there is a higher likelihood of their expression following infection, immunization or other environmental triggers. It is generally held that the production of autoantibodies is driven and controlled by cellular and soluble regulatory mechanisms. Peripheral control of self-tolerance, for example, prevents the emergence of pathologic antibodies. Immune changes that may affect these mechanisms occur in pregnancy, HIV infections, lupus, and other autoimmune diseases, and may be responsible for the development of thrombocytopenia. In all such cases of immune dysregulation, it is not uncommon to see antiplatelet antibody production. There is good evidence for the involvement of T cells in autoimmune diseases, but the T cells responsible for loss of self-tolerance in children with ITP are more difficult to isolate than the platelet autoantibodies. The specific T cells that trigger the disease and their initial target antigens are difficult to identify due to a phenomenon called epitope spreading. At the onset, the T-cell response may be directed against a specific, infectious antigenic epitope, but over time the T cells expand and diversify. New T-cell clones emerge that react with other parts of the same protein or with other molecules in the damaged or activated platelet, stimulating the production of autoreactive B cells previously tolerant to these epitopes.3–5
CYTOKINE PROFILE The cytokine profile in an individual is important in immune regulation, in particular for the primordial T helper lymphocyte precursor, Th0 cell, to differentiate into the Th1 (proinflammatory) or Th2 (down regulator) subsets.6,7 Patients with acute ITP have low levels of interleukin (IL)-4 and IL-6, a profile that is similar to that in children with acute onset of diabetes and arthritis.8 IL-4 is noted for turning off the proinflammatory response, commonly associated with a Th2 response. Hence, in its absence, T cells are frozen in the Th1 or proinflammatory mode. In children, low levels of IL-4 and IL-6 are responsible for the increased expression of HLA-DR Class II molecules on platelet surfaces, a situation very similar to adult, chronic ITP. Additionally, young platelets also c °
2002, Elsevier Science Ltd. All rights reserved.
Blood Reviews (2002) 16, 27–29
doi: 10.1054/blre.2001.0177, available online at http://www.idealibrary.com on
27
Nugent express other immunogenic molecules important in antigen presentation. The plasma cell, an immunoglobulin-producing B cell, is physiologically present in very small numbers. The majority of B cells are in the presecretory state, in which, they are excellent antigen-presenting cells. Unlike macrophages that process large portions of cellular material, the B cell does a more efficient job of antigen presentation than macrophages or dendritic cells.9 Via their surface immunoglobulin molecules, B cells can process antigens and present the peptides in context of the MHC molecules on their surface to T cells. This interaction between T and B cells induces resting B cells to proliferate and produce immunoglobulin, whether it is in response to viruses, or naturally occurring autoantibodies directed against aging platelets or other senescent hematopoietic cells.
PLATELETS AS T CELLS A current concept that is being tested in our laboratory is the premise that platelets can act as sham T cells. In their activated state, platelets express CD40L and CD69. In proximity to B cells, the platelets are able to interact with antigens on B-cell surfaces in the context of the immunoglobulin receptor or MHC molecules, producing cytokines such as IL-1. The proinflammatory effect of IL-1 is B-cell proliferation. Thus, platelet antigens may be involved in the stimulation of B cells to produce platelet autoantibodies. Because IL-1 drives the proinflammatory response by suppressing IL-4 production, we tried to determine the effect of platelets in the phytohemagglutinin stimulation of a mixed population of monocytes and in the production of IL-1. When platelets are added to PHA stimulated mononuclear cells there is a significant increase in IL-1 production particularly in the B cell and monocyteenriched fractions. Platelets did not increase the production of γ interferon in the same PHA-stimulated cultures.12 Following viral infections, platelets, by increasing IL-1 production, can be viewed as stimulating autoantibody production. Antigen specificity may determine whether the ITP is chronic or acute, depending on the maturity and effectiveness of the T lymphocyte suppressors and anti-idiotypic antibodies.13 These studies will begin to distinguish the normal versus pathologic responses to environmental triggers in ITP.
THERAPY FOR CHILDHOOD ITP The management of childhood ITP is controversial. Most practices are based on an empiric approach rather than guided by relevant clinical data. Bone marrow aspiration is only indicated if a diagnosis of persistent thrombocytopenia is established or if patients are unresponsive to intravenous immunoglobulin (IVIg). Treatment options are better defined after assessing the risk of hemorrhage. Thus, it is important to differentiate between a simple hemorrhagic purpura of the skin and mucous membrane bleeding. The indication to treat children with acute ITP should depend on clinical signs, symptoms, and quality-of-life issues. An important rationale to treat children is the unpredictable event of intracranial hemorrhage. The event is very rare, and thus there may be value in treating 28
Blood Reviews (2002) 16, 27–29
c °
2002, Elsevier Science Ltd. All rights reserved.
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
only those children exhibiting severe thrombocytopenia or active bleeding regardless of platelet count. Treatment options include IVIg, corticosteroids, anti-D (if the patient is Rh(D)-positive), platelet transfusion for uncontrolled bleeding, and splenectomy. Because up to 70% of the children recover even from severe thrombocytopenia without specific treatment and register platelet counts of 50,000/µL to 100,000/µL within 3 months,14–18 there is an argument to be made for no treatment. The indication for hospitalization should be reserved for cases where the clinical situation demands for such an approach, such as life-threatening bleeding, and the patient should be treated with IVIg, intravenous methylprednisolone, and platelet transfusion. If the patient’s platelet count is <20,000 / µL with mucous membrane bleeding (wet hemorrhage), the patient should be hospitalized and treated with either IVIg, intravenous corticosteroids, oral corticosteroids, or anti-D. With the same platelet count accompanied by mild bleeding (dry hemorrhage) or no bleeding, hospitalization of the patient is optional, and either no treatment or the same treatment as for mucous membrane bleeding is appropriate. If the child is asymptomatic and has a platelet count <20,000 / µL, observation alone may be warranted.19 The excellent response of thrombocytopenic patients to the infusion of high-dose IVIg, anti-D, or antibody to lymphocyte accessory molecules provides strong evidence that immunomodulatory therapy is feasible in ITP. Most physicians concur that Fc-blockade plays a major role in the success of IVIg and anti-D infusions, which induce a rise in platelet count in the majority of patients regardless of age or etiology of ITP. Apart from reducing splenic clearance of platelets, there is evidence that treatment also alters T-cell subsets, interferes with the production of pathologic antibodies, and may produce alterations in cytokine production.
Correspondence to: Diane J. Nugent , MD, Division of Hematology, Hemostasis / Thrombosis Research, Children’s Hospital of Orange County, 455 South Main Street, Orange, CA 92868. E-mail: [email protected]
References 1. Andrade L, Martinez-AC, Coutinho C. Mother-derived selection of immune repertoires: nongenetic transmission of developmental choices. G. Chaouat, ed. The Immunology of the Fetus 187. CRC Press, Boca Raton, FL, 1990. 2. Lemke H, Lange H, Berek C. Maternal immunization modulates the primary immune response to 2-phenyl-oxazolone in BALB/c mice. Eur J Immunol 1994; 24: 3025–3030. 3. Ware RE, Howard TA. Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura. Blood 1993; 82: 2137–2142. 4. Mamula MJ. Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes. Immunol Rev 1998; 164: 231–239. 5. Farris AD, Keech CL, Gordon TP, McCluskey J. Epitope mimics and determinant spreading: pathways to autoimmunity. Cell Mol Life Sci 2000; 57: 569–578.
ITP in childhood 6. Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, Freedman J. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood 1996; 87: 4245 – 4254. 7. Shevack E. Organ-specific autoimmunity, in Paul WE (ed): Fundamental Immunology. 4th ed. Philadelphia, PA, Lippincott-Raven Publishers, 1999; pp 1089–1125. 8. Nugent D, Berman M, Imfeld K, Dadufalza V, Sandborg C. Depressed IL-4 levels in children with acute and chronic immune thrombocytopenia (ITP). FASEB 1998; 12: A609 (abstr). 9. Liang B, Mamula MJ. Molecular mimicry and the role of B lymphocytes in the processing of autoantigens. Cell Mol Life Sci 2000; 57: 561–568. 10. Ziegler SF, Ramsdell F, Alderson MR. The activation antigen CD69. Stem Cells 1994; 12: 456 – 465. 11. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591–594.
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .
12. Nugent D, Imfeld K, Berman M. Cytokine stimulation by platelets and GPIb immunodominant peptides. Thrombo Haemost 2001; 86: 995 (abstr). 13. Semple JW. Immunobiology of T helper cells and antigen-presenting cells in autoimmune thrombocytopenic purpura (ITP). Acta Paediatr Suppl 1998; 424: 41– 45. 14. Lusher JM, Iyer R. Idiopathic thrombocytopenic purpura in children. Semin Thrombo Hemost 1977; 3: 175–199. 15. Lusher JM, Enami A, Ravindranath V, Warrier AI. Idiopathic thrombocytopenic purpura in children. Am J Pediatr Hematol Oncol 1984; 6: 149–157. 16. Walker RW, Walker W. Idiopathic thrombocytopenic purpura, initial illness and long term follow up. Arch Dis Child 1984; 59: 316–322. 17. Medeiros D, Buchanan GR. Major hemorrhage in children with idiopathic thrombocytopenic purpura: immediate response to therapy and long-term outcome. J Pediatr 1998; 133: 334 – 339. 18. Medeiros D, Buchanan GR. Idiopathic thrombocytopenic purpura: beyond consensus. Curr Opin Pediatr 2000; 12: 4 – 9. 19. Kuhne T, Imbach P. Management of children with acute and chronic immune thrombocytopenic purpura. Transfus Sci 1998; 19: 261–268.
c °
2002, Elsevier Science Ltd. All rights reserved.
Blood Reviews (2002) 16, 27–29
29