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Chapter 24 Tumor and transplantation immunology
CHAPTER 24
Tumor and transplantation
immunology
Robert P. Nelson, Jr., MD St. Petersburg and Tampa, Flu.
TUMOR
IMMUNOLOGY
Tumor antigens are proteins, glycoproteins, or glycolipid components expressed on tumor cell surfaces or secreted in the serum of patients with malignant disease. These molecules differ either qualitatively or quantitatively from those found in normal, welldifferentiated tissue and may be identified immunologically with specific antisera or monoclonal antibodies. Tumor antigens are produced by several mechanisms. Oncofetal antigens, which include carcinoembryonic antigen and cx-fetoprotein, result from aberrant control of genes normally expressed during embryonic or fetal development. Oncogenes are cancer genes present in normal tissues, tumors, and tumorigenic retroviral ribonucleic acid (RNA) that encode for products that may be tumor antigens. Viral antigens are membrane constituents on cells that have been transformed by certain deoxyribonucleic acid viruses and RNA retroviruses and are associated with cancer. Human neoplasms associated with viral infections include T cell leukemia, hairy cell leukemia, nasopharyngeal carcinoma, primary hepatoma, cervical cancer, Burkitt’s lymphoma, and Kaposi’s sarcoma. Finally, those tumors that arise without known induction may bear unique antigens or lose normal membrane constituents such as blood group antigens. Highly specific monoclonal antibodies recognize tumor antigens in a wide variety of human malignancies. These antibodies are used to classify leukemias and lymphomas as to their cell origin and stage of differentiation. The common acute lymphocyte leukemia antigen (CDlO), or CALLA, identifies an early B cell that represents leukemia previously thought of as “non-B, non-T.” Monoclonal antibodies may also be radiolabeled and used with imaging equipment such as computed axial tomography to delineate tumor size and location. The human immune response against tumors consists mainly of specific cytotoxic T cells that lyse cancer cells. Nonspecific responses by natural killer (NK)
From the Departments of Internal Medicine and Pediatrics, Division of Allergy and Immunology, University of South Florida College of Medicine, Tampa, Fla. and All Children’s Hospital, St. Petersburg, Fla.
1108
cells are tumoricidal in vitro, but their in vivo role is not known. Other lymphocytes, known as killer cells, have receptors for immunoglobulins that bind in vitro to antibody-coated tumor cells. These cells kill by a mechanism called antibody-dependent cellular cytotoxicity. Macrophages also kill tumor cells in vitro, but their role in host cancer defense is not well established. Antibodies are produced against tumor antigens in vivo but are probably not clinically significant. Malignancies occur with increased frequency in patients with immunodeficiency disease. Lymphoreticular malignancies occur in 50% of partially reconstituted patients with severe combined immunodeficiency disease (SCID) but are virtually absent in those who are fully reconstituted by marrow transplantation. Epithelial (skin, cervix, stomach, bladder) and endothelial (Kaposi’s sarcoma) tumors also occur with increased frequency in the immunosuppressed. Therapies with monoclonal antibodies with or without conjugated toxins are being investigated. Problems with these approaches include the binding of the monoclonal antibody to normal cells and the development of antibodies against the murine monoclonal antibodies, which prevents antitumor activity. During autologous transplantation, tumor cells such as neuroblastoma may be removed from human bone marrow by purging with monoclonal antibodies before marrow reinfusion. Nonspecific immune stimulation with bacillus Calmette-Guerin or adjuvant Cor;vnebacterium parvum has been clinically disappointing. Biologic response modifiers such as recombinant cytokines are now a part of the immunologic armamentarium against tumors. Interferon alpha is effective against hairy cell leukemia, chronic myelogenous leukemia, and Kaposi’s sarcoma. The combination of interleukin-2 and activated, reinfused autologous lymphocytes partially shrinks tumors in some individuals. CLINICAL TRANSPLANTATION, TRANSPLANTATION IMMUNOLOGY, GRAFT-VERSUS-HOST REACTIONS
AND
Corneal, skin, bone marrow, renal, cardiac, and liver tissues are transplanted to treat organ failure. Syngeneic, allogeneic, and autologous tissues are used as grafts. The major histocompatibility complex
Tumor and transplantation
VIJL:JME 84 RIIJWSBEF ti dAR7 7
(MHC) gene\ located on chromosome 6 encode for proteins tanttgens) that determine the survival of transplanted tissues. Class I antigens, encoded by human leukocyte antigen (HLA)-A, B. and C genetic loci. are present on nearly all nucleated cells. Specific cytotoxic 7 dells recognize class I antigens in the context of attack against virus-infected cells, tumors. and allog~eneic tissues. Multiple HLA-D loci encode for MHC cla\s II antigens, which are expressed only on antigen-presenting cells, B cells, activated T cells. and thyme epithelium. MHC class II antigens initiate graft-versus-host (GVH) reactions, activate rejection reactions against grafts, and stimulate T cell proliferutmn in mixed lymphocyte culture reactions. (iraft rejection occurs with increasing frequency and rate a:>donor-recipient antigen disparity increases. In solid organ transplantation, hyperacute rejection reactions (occurring minutes to days after transplantation) are mediated by preformed antibodies. Accelerated rejection reactions (within a few days) are mediated by sensitized T ,:ells. Acute rejection reactions (one to several weeks) are mediated by cells (steroid responsive) or by newly formed antibodies (steroid unresponsive) and are distinguished by renal biopsy. Chronic rejection (over many months) is mediated by both cellular and humoral responses and is often resistant to immunosuppressive therapy. The occurrence of graft rejection is limited by matching histocompatibility antigens in all transplants and avoiding ABO and Lewis blood group incompatibilities with renal grafts. Transplantation anti&ens are identified by HLA testing with antisera from regular blood donors and multiparous women. Preformed antibodies can be detected by screening recipient scra against lymphocytes from multiple normal subjects as well as the donor’s in a “cross-match” assay. Transfusions of whole blood improve graft survival in solid organ grafts, probably by generating recipient suppressor cells ti) class I antigens. Immunosuppressive agents are used in most organ transplants, depending on protocol and graft type. Methylpredniaolone, azathioprine. and cyclosporine are used in various combinations to enhance engraftment and limit GVH reactions. Opportunistic infection\ and the occurrence of malignancies may complicate the use of these drugs. GVH reactions occur after bone marrow transplantation. when immunologically competent donor cells become sensitized to class XI and probably non-HLA or “minor histocompatibility antigens” in the recipient or after blood transfusions in severely immunodeficient patients. In acute GVH disease, target tissues include skin, gastrointestinal tract, and liver. Acute GVH disease is clinically staged according
inlmtipdogy
1109
to disease severity and is fatal in approximately 25% of cases. Severe acute GVH disease may be prevented by purging donor lymphocytcb (from a bone marrow graft) or by using irnrnuno\uppressive drugs, such as glucocorticosteroids. methotrexate. or cyclosporine. Chronic GVH disease (more than 100 days after transplant) occurs in 25% of bone marrow recipients, mostly in those who developed acute GC H disease. Target organs are skin, liver. joint. lacrimal/salivary glands, and lungs. Drug treatments include glucocorticosteroids and azathioprine. IMMUNE
RECONSTITUTION
immune reconstitution is the replacement of deficient humoral or cellular immunologic functions. Replacement antibodies are indicated for patients with agammaglobulinemia, X-linked immune deficiency. common variable hypogammaglobulinemia. antibody deficiency with near-normal immunoglobuIins. Wiskott-Aldrich syndrome. and all forms of SCID. Immunoglobulin replacement is not indicated for transient hypogammaglobulinemia of infancy and is contraindicated in isolated IgA deticiency. Replacement therapy for isolated subclass deficiency is currently under investigation. In mo\r patients. normal trough IgG levels may be achieved by the intravenous administration of -NO mg / kg! month Intramuscular replacement with immune serum globulin is an alternative. Side effects are fever. myalgiax. Aank and back pain, rashes. and more severe anaphyiactoid reactions. Equal doses of intramuscular or intravenous products prevent infections equally well. Compared with intramuscular immunoglobulin, the intravenous product may be more effective when given at higher doses, is lest painful. has fewer severe anaphylactoid reactions, and can be used in patients with bleeding tendencies. Intravenous administration is. houe\,er. much more zxpensivt Patients with severe forms of cel!ular immune deticiency are treated with immunocompetent bone marrow tissue from MHC-compatible or haploidentical donors. Depletion of post-thymic T cells from partially matched donor marrow with soybean lectin and \heep erythrocytes or monoclonal anti&T cell antibodies plus complement leaves stem cells intact for transplantation to those patients who do not have matched siblings. All transplanted patients have in vivo immunologic deficiences during the first 6 rnonths after transplantation. In vitro measurements of immunologic functions such as mixed lymphocyte culture, proliferative responses to mitopenx, 7’ and B cell enumeration, natural killer activity. and cellular cytatoxicity
return
to normal
before in vivL> reconsti-
J. ALLERGY
1110 Nelson
tution is achieved. Patients with chronic GVH disease demonstrate decreased ability to form antibodies to neoantigens and pneumococcal polysaccharides, do not switch normally from IgM to IgG production, and suffer from recurrent bacterial infections. Thymus-dependent immune functions may be reconstituted by transplantation of thymus obtained from fetuses at 10 to 16 weeks of gestation or of thymic epithelium. This method has been used in children with DiGeorge syndrome. Some patients with adenosine deaminase or purinenucleoside phosphorylase deficiency have been treated with frozen irradiated erythrocytes to partially replace the missing enzyme. Gene therapy is the insertion of a functional gene for a missing enzyme into a deficient host cell, such as those in adenosine deaminase-deficient patients. In the near future, autologous bone marrow harvest followed by gene introduction and reinfusion may be used to treat such patients. Immunomodulating compounds include biologic substances and chemically defined agents that alter immunologic function. Immunostimulatory biologic agents include thymic factors, lymphokines, interferons, and leukocyte extracts (transfer factor). Chemically defined immunostimulating agents include inosine pranobex and muramyl dipeptide. These compounds stimulate immunologic functions in vitro and are currently being investigated for their clinical usefulness .
Tumor and transplantation immunology HLA-B genetic loci encode for proteins present on: a. B cells b. Macrophages c. Neutrophils d. Activated T cells Explanation: HLA-B genetic loci are part of the MHC complex that codes for class I antigens (HLA-A, HLA-B, and HLA-C). These antigens are present on virtually all nucleated cells. Answer: All are correct. Reference: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunological diseases. JAMA 1987; 258:2993-3000. HLA-D loci encode for: a. Proteins on antigen-presenting cells b. Proteins present on neutrophils
CLIN. IMMUNOL. DECEMBER 1989
c. Class II antigens d. Proteins on erythrocytes Explanation: HLA-D genetic loci encode for class II histocompatibility antigens present only on antigenpresenting cells, B cells, activated T cells, and thymic epithelial cells. Answer: a and c. Reference: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic andimmunological diseases. JAMA 1987; 258:2993-3000. Acute GVH disease: a. Can be prevented by irradiating blood products b. Affects mainly the kidneys c. Is minimized by depleting T cells from donor marrow d. Occurs 24 to 48 hours after transplantation Explanation: GVH disease occurs after bone marrow transplantation and occasionally after blood transfusion to patients with SCID. Acute GVH disease develops 7 to 14 days after the infusion of cells, is mediated by mature lymphocytes, and affects mainly the gastrointestinal tract, skin, and liver. GVH disease can be prevented by irradiating blood products before transfusing immunodeficient patients. Acute GVH disease may be minimized during bone marrow transplantation by using matched donors, T cell depletion of the marrow before infusing into the recipient, or using immunosuppresive drugs such as cyclosporine, methotrexate, or prednisone in the peritransplant period. Answer: a and c. References: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunologic diseases. JAMA 1987; 258:2993-3000; Bach FH. Current concepts: immunology, transplantation immunology. N Engl J Med 1987;317:489-92. Solid organ graft rejection may be minimized or prevented by: a. Matching histocompatibility antigens b. Multiple whole blood transfusions before transplantation c. Testing recipient for preformed antibodies directed against the donor’s transplantation antigens
VOLclME NUMBER
84 6. PART 2
d. Testing recipient for preformed antibodies directed against HLA from multiple donors Explanation: All grafts, both solid organ (kidney) and bone marrow, “take” better with optimally matched donor-recipient tissues. Pretransplant blood transfusions affect graft survival differently, depending on the transplanted tissue. Patients with aplastic anemia who receive multiple transfusions before transplantation become sensitive to HLA, which results in increased graft rejection. Whole blood transfusion befort renal transplantation improves graft survival. The presence of high-titer preformed antibodies to HLA present on multiple donor test panels and, more specifically. to those antigens from the donor predict solid organ rejection reactions of the immediate hyperacute variety.
Answer: All are correct. Ryferencr: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunological diseases. JAMA 1987; 258:2993-3000. Tumor antigens may be: a. Oncofetal antigens such as a-fetoprotein b. Ocogene products c. Viral antigens d. Normal cell products
Tumor
and transplantation
immunology
1111
antigens. Viral antigens may be tumor antigens detected in those cancers associated with virus infections. Most tumor markers are actually normal cell products produced in abnormal amounts. Answer: All are correct. References: Kagan JM, Fahey JL. Tumor immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunologic diseases. JAMA 1987; 258:2988-92; Thomson DMP, Major PP. Shuster J, Gold P. Tumor immunology. In: Samter M, Talmage DW. Frank MM, Austen KF, Claman HN, eds. Immunological diseases. Boston: Little. Brown, 1988: 521-51. Patients with which of the following diseases are candidates for immunoglobulin replacement therapy? a. Common variable hypogammaglobulinemia b. Wiskott-Aldrich syndrome c. SCID d. Isolated IgA deficiency Explanation: Immunoglobulin replacement is indicated for diseases characterized by impairment of specific IgG immunoglobulin production. These include Wiskott-Aldrich syndrome and SCID but not necessarily IgG subclass deficiency. Replacement therapy in isolated IgA deficiency is contraindicated. Answer: a, b, and c.
Explanation: Tumor antigens may be oncofetal antigens that are expressed normally during embryonic development. Oncogenes that occur in normal chromosomes and the genetic material of cancer cells and retroviruses encode for products that may be tumor
Reference: Buckley RH. Immunodeficiency diseases. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunologic diseases. JAMA 1987;258: 2841-50.
Tumor and transplantation
immunology
Robert P. Nelson, Jr., MD St. Petersburg and Tampa, Flu.
TUMOR
IMMUNOLOGY
Tumor antigens are proteins, glycoproteins, or glycolipid components expressed on tumor cell surfaces or secreted in the serum of patients with malignant disease. These molecules differ either qualitatively or quantitatively from those found in normal, welldifferentiated tissue and may be identified immunologically with specific antisera or monoclonal antibodies. Tumor antigens are produced by several mechanisms. Oncofetal antigens, which include carcinoembryonic antigen and cx-fetoprotein, result from aberrant control of genes normally expressed during embryonic or fetal development. Oncogenes are cancer genes present in normal tissues, tumors, and tumorigenic retroviral ribonucleic acid (RNA) that encode for products that may be tumor antigens. Viral antigens are membrane constituents on cells that have been transformed by certain deoxyribonucleic acid viruses and RNA retroviruses and are associated with cancer. Human neoplasms associated with viral infections include T cell leukemia, hairy cell leukemia, nasopharyngeal carcinoma, primary hepatoma, cervical cancer, Burkitt’s lymphoma, and Kaposi’s sarcoma. Finally, those tumors that arise without known induction may bear unique antigens or lose normal membrane constituents such as blood group antigens. Highly specific monoclonal antibodies recognize tumor antigens in a wide variety of human malignancies. These antibodies are used to classify leukemias and lymphomas as to their cell origin and stage of differentiation. The common acute lymphocyte leukemia antigen (CDlO), or CALLA, identifies an early B cell that represents leukemia previously thought of as “non-B, non-T.” Monoclonal antibodies may also be radiolabeled and used with imaging equipment such as computed axial tomography to delineate tumor size and location. The human immune response against tumors consists mainly of specific cytotoxic T cells that lyse cancer cells. Nonspecific responses by natural killer (NK)
From the Departments of Internal Medicine and Pediatrics, Division of Allergy and Immunology, University of South Florida College of Medicine, Tampa, Fla. and All Children’s Hospital, St. Petersburg, Fla.
1108
cells are tumoricidal in vitro, but their in vivo role is not known. Other lymphocytes, known as killer cells, have receptors for immunoglobulins that bind in vitro to antibody-coated tumor cells. These cells kill by a mechanism called antibody-dependent cellular cytotoxicity. Macrophages also kill tumor cells in vitro, but their role in host cancer defense is not well established. Antibodies are produced against tumor antigens in vivo but are probably not clinically significant. Malignancies occur with increased frequency in patients with immunodeficiency disease. Lymphoreticular malignancies occur in 50% of partially reconstituted patients with severe combined immunodeficiency disease (SCID) but are virtually absent in those who are fully reconstituted by marrow transplantation. Epithelial (skin, cervix, stomach, bladder) and endothelial (Kaposi’s sarcoma) tumors also occur with increased frequency in the immunosuppressed. Therapies with monoclonal antibodies with or without conjugated toxins are being investigated. Problems with these approaches include the binding of the monoclonal antibody to normal cells and the development of antibodies against the murine monoclonal antibodies, which prevents antitumor activity. During autologous transplantation, tumor cells such as neuroblastoma may be removed from human bone marrow by purging with monoclonal antibodies before marrow reinfusion. Nonspecific immune stimulation with bacillus Calmette-Guerin or adjuvant Cor;vnebacterium parvum has been clinically disappointing. Biologic response modifiers such as recombinant cytokines are now a part of the immunologic armamentarium against tumors. Interferon alpha is effective against hairy cell leukemia, chronic myelogenous leukemia, and Kaposi’s sarcoma. The combination of interleukin-2 and activated, reinfused autologous lymphocytes partially shrinks tumors in some individuals. CLINICAL TRANSPLANTATION, TRANSPLANTATION IMMUNOLOGY, GRAFT-VERSUS-HOST REACTIONS
AND
Corneal, skin, bone marrow, renal, cardiac, and liver tissues are transplanted to treat organ failure. Syngeneic, allogeneic, and autologous tissues are used as grafts. The major histocompatibility complex
Tumor and transplantation
VIJL:JME 84 RIIJWSBEF ti dAR7 7
(MHC) gene\ located on chromosome 6 encode for proteins tanttgens) that determine the survival of transplanted tissues. Class I antigens, encoded by human leukocyte antigen (HLA)-A, B. and C genetic loci. are present on nearly all nucleated cells. Specific cytotoxic 7 dells recognize class I antigens in the context of attack against virus-infected cells, tumors. and allog~eneic tissues. Multiple HLA-D loci encode for MHC cla\s II antigens, which are expressed only on antigen-presenting cells, B cells, activated T cells. and thyme epithelium. MHC class II antigens initiate graft-versus-host (GVH) reactions, activate rejection reactions against grafts, and stimulate T cell proliferutmn in mixed lymphocyte culture reactions. (iraft rejection occurs with increasing frequency and rate a:>donor-recipient antigen disparity increases. In solid organ transplantation, hyperacute rejection reactions (occurring minutes to days after transplantation) are mediated by preformed antibodies. Accelerated rejection reactions (within a few days) are mediated by sensitized T ,:ells. Acute rejection reactions (one to several weeks) are mediated by cells (steroid responsive) or by newly formed antibodies (steroid unresponsive) and are distinguished by renal biopsy. Chronic rejection (over many months) is mediated by both cellular and humoral responses and is often resistant to immunosuppressive therapy. The occurrence of graft rejection is limited by matching histocompatibility antigens in all transplants and avoiding ABO and Lewis blood group incompatibilities with renal grafts. Transplantation anti&ens are identified by HLA testing with antisera from regular blood donors and multiparous women. Preformed antibodies can be detected by screening recipient scra against lymphocytes from multiple normal subjects as well as the donor’s in a “cross-match” assay. Transfusions of whole blood improve graft survival in solid organ grafts, probably by generating recipient suppressor cells ti) class I antigens. Immunosuppressive agents are used in most organ transplants, depending on protocol and graft type. Methylpredniaolone, azathioprine. and cyclosporine are used in various combinations to enhance engraftment and limit GVH reactions. Opportunistic infection\ and the occurrence of malignancies may complicate the use of these drugs. GVH reactions occur after bone marrow transplantation. when immunologically competent donor cells become sensitized to class XI and probably non-HLA or “minor histocompatibility antigens” in the recipient or after blood transfusions in severely immunodeficient patients. In acute GVH disease, target tissues include skin, gastrointestinal tract, and liver. Acute GVH disease is clinically staged according
inlmtipdogy
1109
to disease severity and is fatal in approximately 25% of cases. Severe acute GVH disease may be prevented by purging donor lymphocytcb (from a bone marrow graft) or by using irnrnuno\uppressive drugs, such as glucocorticosteroids. methotrexate. or cyclosporine. Chronic GVH disease (more than 100 days after transplant) occurs in 25% of bone marrow recipients, mostly in those who developed acute GC H disease. Target organs are skin, liver. joint. lacrimal/salivary glands, and lungs. Drug treatments include glucocorticosteroids and azathioprine. IMMUNE
RECONSTITUTION
immune reconstitution is the replacement of deficient humoral or cellular immunologic functions. Replacement antibodies are indicated for patients with agammaglobulinemia, X-linked immune deficiency. common variable hypogammaglobulinemia. antibody deficiency with near-normal immunoglobuIins. Wiskott-Aldrich syndrome. and all forms of SCID. Immunoglobulin replacement is not indicated for transient hypogammaglobulinemia of infancy and is contraindicated in isolated IgA deticiency. Replacement therapy for isolated subclass deficiency is currently under investigation. In mo\r patients. normal trough IgG levels may be achieved by the intravenous administration of -NO mg / kg! month Intramuscular replacement with immune serum globulin is an alternative. Side effects are fever. myalgiax. Aank and back pain, rashes. and more severe anaphyiactoid reactions. Equal doses of intramuscular or intravenous products prevent infections equally well. Compared with intramuscular immunoglobulin, the intravenous product may be more effective when given at higher doses, is lest painful. has fewer severe anaphylactoid reactions, and can be used in patients with bleeding tendencies. Intravenous administration is. houe\,er. much more zxpensivt Patients with severe forms of cel!ular immune deticiency are treated with immunocompetent bone marrow tissue from MHC-compatible or haploidentical donors. Depletion of post-thymic T cells from partially matched donor marrow with soybean lectin and \heep erythrocytes or monoclonal anti&T cell antibodies plus complement leaves stem cells intact for transplantation to those patients who do not have matched siblings. All transplanted patients have in vivo immunologic deficiences during the first 6 rnonths after transplantation. In vitro measurements of immunologic functions such as mixed lymphocyte culture, proliferative responses to mitopenx, 7’ and B cell enumeration, natural killer activity. and cellular cytatoxicity
return
to normal
before in vivL> reconsti-
J. ALLERGY
1110 Nelson
tution is achieved. Patients with chronic GVH disease demonstrate decreased ability to form antibodies to neoantigens and pneumococcal polysaccharides, do not switch normally from IgM to IgG production, and suffer from recurrent bacterial infections. Thymus-dependent immune functions may be reconstituted by transplantation of thymus obtained from fetuses at 10 to 16 weeks of gestation or of thymic epithelium. This method has been used in children with DiGeorge syndrome. Some patients with adenosine deaminase or purinenucleoside phosphorylase deficiency have been treated with frozen irradiated erythrocytes to partially replace the missing enzyme. Gene therapy is the insertion of a functional gene for a missing enzyme into a deficient host cell, such as those in adenosine deaminase-deficient patients. In the near future, autologous bone marrow harvest followed by gene introduction and reinfusion may be used to treat such patients. Immunomodulating compounds include biologic substances and chemically defined agents that alter immunologic function. Immunostimulatory biologic agents include thymic factors, lymphokines, interferons, and leukocyte extracts (transfer factor). Chemically defined immunostimulating agents include inosine pranobex and muramyl dipeptide. These compounds stimulate immunologic functions in vitro and are currently being investigated for their clinical usefulness .
Tumor and transplantation immunology HLA-B genetic loci encode for proteins present on: a. B cells b. Macrophages c. Neutrophils d. Activated T cells Explanation: HLA-B genetic loci are part of the MHC complex that codes for class I antigens (HLA-A, HLA-B, and HLA-C). These antigens are present on virtually all nucleated cells. Answer: All are correct. Reference: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunological diseases. JAMA 1987; 258:2993-3000. HLA-D loci encode for: a. Proteins on antigen-presenting cells b. Proteins present on neutrophils
CLIN. IMMUNOL. DECEMBER 1989
c. Class II antigens d. Proteins on erythrocytes Explanation: HLA-D genetic loci encode for class II histocompatibility antigens present only on antigenpresenting cells, B cells, activated T cells, and thymic epithelial cells. Answer: a and c. Reference: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic andimmunological diseases. JAMA 1987; 258:2993-3000. Acute GVH disease: a. Can be prevented by irradiating blood products b. Affects mainly the kidneys c. Is minimized by depleting T cells from donor marrow d. Occurs 24 to 48 hours after transplantation Explanation: GVH disease occurs after bone marrow transplantation and occasionally after blood transfusion to patients with SCID. Acute GVH disease develops 7 to 14 days after the infusion of cells, is mediated by mature lymphocytes, and affects mainly the gastrointestinal tract, skin, and liver. GVH disease can be prevented by irradiating blood products before transfusing immunodeficient patients. Acute GVH disease may be minimized during bone marrow transplantation by using matched donors, T cell depletion of the marrow before infusing into the recipient, or using immunosuppresive drugs such as cyclosporine, methotrexate, or prednisone in the peritransplant period. Answer: a and c. References: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunologic diseases. JAMA 1987; 258:2993-3000; Bach FH. Current concepts: immunology, transplantation immunology. N Engl J Med 1987;317:489-92. Solid organ graft rejection may be minimized or prevented by: a. Matching histocompatibility antigens b. Multiple whole blood transfusions before transplantation c. Testing recipient for preformed antibodies directed against the donor’s transplantation antigens
VOLclME NUMBER
84 6. PART 2
d. Testing recipient for preformed antibodies directed against HLA from multiple donors Explanation: All grafts, both solid organ (kidney) and bone marrow, “take” better with optimally matched donor-recipient tissues. Pretransplant blood transfusions affect graft survival differently, depending on the transplanted tissue. Patients with aplastic anemia who receive multiple transfusions before transplantation become sensitive to HLA, which results in increased graft rejection. Whole blood transfusion befort renal transplantation improves graft survival. The presence of high-titer preformed antibodies to HLA present on multiple donor test panels and, more specifically. to those antigens from the donor predict solid organ rejection reactions of the immediate hyperacute variety.
Answer: All are correct. Ryferencr: Kirkpatrick CH. Transplantation immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunological diseases. JAMA 1987; 258:2993-3000. Tumor antigens may be: a. Oncofetal antigens such as a-fetoprotein b. Ocogene products c. Viral antigens d. Normal cell products
Tumor
and transplantation
immunology
1111
antigens. Viral antigens may be tumor antigens detected in those cancers associated with virus infections. Most tumor markers are actually normal cell products produced in abnormal amounts. Answer: All are correct. References: Kagan JM, Fahey JL. Tumor immunology. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunologic diseases. JAMA 1987; 258:2988-92; Thomson DMP, Major PP. Shuster J, Gold P. Tumor immunology. In: Samter M, Talmage DW. Frank MM, Austen KF, Claman HN, eds. Immunological diseases. Boston: Little. Brown, 1988: 521-51. Patients with which of the following diseases are candidates for immunoglobulin replacement therapy? a. Common variable hypogammaglobulinemia b. Wiskott-Aldrich syndrome c. SCID d. Isolated IgA deficiency Explanation: Immunoglobulin replacement is indicated for diseases characterized by impairment of specific IgG immunoglobulin production. These include Wiskott-Aldrich syndrome and SCID but not necessarily IgG subclass deficiency. Replacement therapy in isolated IgA deficiency is contraindicated. Answer: a, b, and c.
Explanation: Tumor antigens may be oncofetal antigens that are expressed normally during embryonic development. Oncogenes that occur in normal chromosomes and the genetic material of cancer cells and retroviruses encode for products that may be tumor
Reference: Buckley RH. Immunodeficiency diseases. In: Lackey RF, Bukantz SC, eds. Primer on allergic and immunologic diseases. JAMA 1987;258: 2841-50.