White Blood Cell Deficiencies
The blood contains several types of white blood cells, also called leukocytes, which are an important part of the body's immune defense system. White blood cells include macrophages, granulocytes and lymphocytes. The average adult male has about 7,500 white blood cells/mm3. This number may increase dramatically following an infection, and may decrease in people with immunodeficiency diseases such as AIDS. HIV specifically infects and kills certain types of white blood cells (CD4 T-cells and macrophages).
All white blood cells develop from stem cells in the bone marrow. As stem cells differentiate, they give rise to different lineages of cells. The myelocytic lineage develops into monocytes, macrophages and various types of granulocytes. The lymphocytic lineage develops into B-cells and T-cells.
A low white blood cell count is referred to as leukopenia. Deficiencies of all types of white blood cells can be caused by bone marrow suppression. However, it is generally more useful to look at numbers of specific types of white blood cells, rather than at the white cell population as a whole.
Monocytes and Macrophages
Monocytes are large blood cells that live for a short time in the circulating blood before they migrate into the tissues of the body and mature into macrophages. Macrophages are large scavenger cells that target different types of "enemies." Many macrophages reside in the lymph nodes and spleen, and specialized macrophages protect the skin, lungs, intestines, liver, brain and other tissues. Macrophages engulf and digest foreign microorganisms (e.g., bacteria, fungi, protozoans), allergens, tumor cells and cellular debris, a process known as phagocytosis. Macrophages then display pieces of these digested microorganisms and cells on their surface, where they can be recognized by helper T-cells. For this reason, macrophages are known as antigen-presenting cells.
The production of new monocytes and the activation of macrophages are controlled by cytokines, in particular macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These messengers are released by other immune system cells -- in particular helper T-cells -- when an invader or abnormal cell is encountered. Macrophages in turn release their own cytokines which stimulate other immune system components.
Bone marrow suppression can lead to a shortage of monocytes and macrophages. In addition, low levels of certain cytokines can affect the proliferation of monocytes and the proper functioning of macrophages. However, there is no common blood deficiency specifically characterized by a low number of monocytes or macrophages.
Neutrophils and Other Granulocytes
Granulocytes are a class of white blood cells that contain granules of chemicals. The 3 types of granulocytes are neutrophils, eosinophils and basophils. Mast cells are tissue-based cells related to basophils. Granulocytes are produced and stored in the bone marrow until they are released by cytokines. These cells defend against bacteria, fungi, parasites and allergens.
Neutrophils are phagocytic cells that engulf harmful agents. After a neutrophil has ingested a foreign agent, toxic chemicals are released from the cell's granules to kill and digest the invader. Neutrophils are the most common type of granulocyte and are the mainstay of the body's defense against bacteria and fungi. The number of neutrophils may increase dramatically when the body is fighting an infection or is otherwise under stress. In some cases, immature neutrophils called bands may be released into the bloodstream. Neutrophil proliferation, maturation and release are stimulated by the cytokines granulocyte colony-stimulating factor (G-CSF) and GM-CSF, which are produced by other immune system cells including macrophages and CD4 T-cells. An abnormally low number of neutrophils is known as neutropenia.
Eosinophils and basophils are the least common types of white blood cells. Both release chemicals that are involved in allergic reactions. In addition, eosinophils can engulf parasites. Although bone marrow suppression reduces the number of eosinophils and basophils, specific deficiencies of these types of cells are not common. The condition referred to as granulocytopenia in practice refers to a shortage of neutrophils, not eosinophils or basophils.
Because neutrophils attack invading microorganisms, people with a deficiency of these cells are prone to infections, especially by bacteria. Early signs of neutropenia include fever, fatigue, sore throat, mouth ulcers and fungal infections of the mouth or vagina. A healthy person normally has 3,000-7,000 neutrophils/mm3. A count of 1,000-2,000 neutrophils/mm3 is considered mild neutropenia. Severe neutropenia is less than 500 neutrophils/mm3.
Neutropenia may result from damage to bone marrow stem cells or prescursors. Because the short-lived neutrophils are among the most rapidly proliferating cells, they are especially sensitive to radiation therapy and bone marrow-suppressing drugs. Neutropenia may also be due to genetic defects or autoimmune conditions that lead to the destruction of neutrophils. Temporary neutropenia lasting several weeks may follow a bacterial or viral infection.
People with HIV/AIDS often develop neutropenia, usually some time after their CD4 T-cell count starts to decline. This is often due to the use of bone-marrow suppressing anti-HIV drugs. Changing drugs or reducing doses may effectively reverse a decline in neutrophil numbers, especially in the case of combination regimens in which more than one drug suppresses the bone marrow, a phenomenon known as additive toxicity.
Injections of genetically engineered G-CSF (filgrastim; brand name Neupogen) and GM-CSF (sargramostim; brand names Leukine and Prokine) are used to treat neutropenia. G-CSF is FDA-approved for use by people receiving bone marrow-suppressing cancer chemotherapy, bone marrow transfer patients and people with severe chronic neutropenia. A recent study at 30 medical centers in the U.S. and Canada confirmed that use of G-CSF in people with HIV led to rapid increases in neutrophil counts and was associated with 31% fewer bacterial infections and a significantly lower risk of death. The typical dose of G-CSF is 5 micrograms per kilogram of body weight per day injected under the skin or directly into a vein. Frequency and duration of treatment are based on how well a person responds. Side effects of G-CSF include bone pain, fever, mouth sores and elevated liver enzymes.
GM-CSF is approved for stimulation of bone marrow precursor cells following a bone marrow transfer. It has also been tested in clinical trials in people with HIV/AIDS experiencing drug-related bone marrow suppression. GM-CSF works at an earlier stage of blood cell differentiation than G-CSF and stimulates the production of macrophages as well as granulocytes. Unfortunately, the stimulation of macrophages may also promote the replication of HIV contained in these cells. The typical dose of GM-CSF is 250 mg per square meter of body surface area per day. Dose and duration of treatment are adjusted based on individual response. Side effects include fever, chills, headache, skin rash, tissue swelling, muscle and bone pain, and elevated liver enzymes. Because it has fewer side effects, G-CSF is generally preferred over GM-CSF for the treatment of neutropenia.
Although transfusions of neutrophils are sometimes used to treat severe neutropenia, they are impractical because neutrophils have such a brief life span. In some cases, people with neutropenia are given preventive antibiotics to reduce their risk of infection.
B-cells, T-cells and natural killer cells make up the class of white blood cells known as lymphocytes. The action of B-cells and T-cells is referred to as specific immunity because each cell targets a specific antigen (a substance that stimulates an immune response). Natural killer cells are non-specific and attack a wide range of virus-infected cells and tumor cells. Like other blood cells, lymphocytes are produced in the bone marrow. B-cells mature in the bone marrow, while T-cells migrate and mature in the thymus, an immune system organ in the chest. As they mature, each B-cell and T-cell learns to recognize a single, specific antigen. Most mature lymphocytes reside in the lymph nodes, spleen and other immune tissues until they are called into action. When lymphocytes recognize their particular antigen, they release cytokines that stimulate further immune activity.
A reduced number of lymphocytes in the blood is called lymphocytopenia or lymphopenia. This condition may result from bone marrow suppression that affects all types of blood cells, but there are also specific deficiencies of B-cells and T-cells. Lymphocytopenia may be caused by lack of the trace element zinc, long-term heavy alcohol consumption and certain infectious diseases (e.g., HIV disease, viral hepatitis, influenza, tuberculosis). In addition, B-cells and T-cells may fail to differentiate from their common precursor cell.
B-Cells and B-Cell Deficiencies
B-cells are the key players in the humoral arm of the immune system. They make up about 15% of the lymphocytes in circulating blood. B-cells have antibodies on their surface. When they encounter an invading microorganism that matches these antibodies, they alert helper T-cells. The helper T-cells in turn release cytokines that instruct the B-cells to develop into plasma cells. Plasma cells then produce antibodies that attack the invader. After this response has run its course, some of the B-cells remain as memory cells that can respond quickly to future invasions by the same microorganism.
There are several disorders characterized by a deficiency of B-cells, failure of precursor cells to evolve into mature B-cells, failure of B-cells to develop into plasma cells, or reduced production of various types of antibodies.
Gamma globulin is the usual treatment for low antibody levels. Gamma globulin is an injected preparation of antibodies, and may consist of either a variety of different types of antibodies or antibodies against a single, specific microorganism. In severe and persistent cases of B-cell deficiency, a bone marrow transfer may be done.
T-Cells and HIV Disease
T-cells are the basis of the cell-mediated arm of the immune system. T-cells make up about 75% of circulating lymphocytes. There are various types of T-cells. Helper T-cells -- also known as CD4 cells because they carry a cell surface receptor called CD4 -- coordinate the immune response. When helper T-cells recognize antigens displayed by antigen-presenting cells, they release cytokines that regulate the production and activation of other immune cells, including macrophages, B-cells and other types of T-cells. Activated CD4 T-cells proliferate in the lymph nodes.
Two types of T-cells carry a cell surface receptor called CD8. Suppressor T-cells help regulate the body's immune response and "turn off" a response that is no longer needed. Killer T-cells, also known as cytotoxic T-lymphocytes (CTL), recognize and kill tumor cells and cells that are infected by viruses.
HIV infects CD4 T-cells, and the progressive loss of these cells is a hallmark of AIDS. HIV promotes CD4 T-cell death in a variety of ways. Over time, reduction in the number of helper T-cells leads to a breakdown of the immune system and a susceptibility to various opportunistic infections and cancers.
A healthy adult normally has about 800-1,200 CD4 T-cells/mm3. Numbers may be considerably higher in children. In people with untreated HIV, the CD4 T-cell count often decreases dramatically as disease progresses. When the number falls below 200 cells/mm3, the immune system has sustained major damage and a person is diagnosed as having AIDS. People with fewer than 50 cells/mm3 are especially susceptible to opportunistic infections.
During the course of HIV disease, the ratio of CD4 cells to CD8 cells shifts. As CD4 cells die off, the result is a relatively higher proportion of CD8 cells. The normal ratio zis 2.0; in people with HIV, the ratio may be reversed.
Helper T-cell production is stimulated by the cytokine intereukin-2, and injected genetically engineered IL-2 (brand name Proleukin) has been studied as a treatment for HIV-related CD4 T-cell deficiencies. Clifford Lane, MD, and colleagues found that in 60 patients given IL-2 for 12 months, CD4 T-cell counts increased by an average of 37 cells/mm3 per month. A study by R. Davey and colleagues presented at the 1996 International Conference on AIDS showed 50-80% increases in CD4 T-cells in people receiving intermittently administered IL-2. Treatment with IL-2 is more effective in people who have more than 200 CD4 cells/mm3, and in fact may be harmful in people with fewer CD4 cells.
Various amounts and dosage schedules of IL-2 have been tried. Typically it is administered intravenously every day for a week, then discontinued for 1-2 months. IL-2 is associated with flu-like side effects including fever, malaise, muscle aches, and sometimes liver and kidney dysfunction. Less frequent administration of IL-2 or injection under the skin rather than into a vein can help lessen side effects. A large, international study of IL-2 (ACTG 328) has recently begun.
Agents like IL-2 that stimulate the proliferation of activated CD4 T-cells can also stimulate the replication of HIV as the T-cells multiply, resulting in increased viral load. IL-2 should only be used in conjunction with potent antiretroviral therapy.
Platelet Deficiencies: Thrombocytopenia
In addition to red and white blood cells, whole blood also contains thrombocytes, better known as platelets. These small cell fragments are involved in normal blood clotting following injury. They form a platelet plug at the site of a damaged blood vessel and produce substances that initiate a cascade of steps that result in blood coagulation and wound healing. Platelets arise from the fragmentation of precursor cells called megakaryocytes, which evolve from stem cells in the bone marrow. Platelet production is stimulated by cytokines called megakaryocyte growth and development factor, IL-11 and thrombopoietin (TPO).
An abnormally low number of platelets is referred to as thrombocytopenia. This condition, as with all blood cell deficiencies, may be caused by bone marrow suppression. Following bone marrow damage, megakaryocytes take a long time to recover, and thrombocytopenia is often the most persistent blood cell deficiency. Thrombocytopenia can also be due to increased destruction of platelets. Thrombocytopenic purpura is a bleeding disorder that results from insufficient platelets. It is characterized by bleeding from small blood vessels, leading to many bruises under the skin. Thrombocytopenic purpura may be acute or chronic. Sometimes the cause of the condition cannot be determined (idiopathic thrombocytopenic purpura), but it often results from an autoimmune response in which antibodies destroy platelets. Thrombocytopenia can also lead to bleeding gums and nosebleeds, and in some cases to bleeding within the skull. Although fewer than 100,000 platelets/mm3 is considered a deficiency, increased bleeding does not usually occur until the number has fallen below 50,000 platelets/mm3.
Rho (d) (brand name WinRho SD) and other injected immunoglobulin (antibody) preparations may be used to treat thrombocytopenia in people with HIV. Immunoglobulin appears to work by preventing clusters of HIV fragments and antibodies from binding to platelets and marking them for destruction. In cases of autoimmune platelet destruction, immune-dampening corticosteroids such as prednisone may be used. Anti-HIV therapy may relieve HIV-related thrombocytic purpura.
Genetically engineered cytokines are a potential treatment for thrombocytopenia. Recombinant thrombopoietin is currently under development. Often people with thrombocytopenia are given transfusions of whole blood or platelets. In persistent cases, platelet transfusions may have to be given every day for an extended period, sometimes for life.
In severe cases of thrombocytopenia, removal of the spleen may be necessary. In the spleen, macrophages remove old platelets from the bloodstream. If the spleen is removed, platelets are allowed to remain in circulation longer.
Blood cell deficiencies once necessitated inconvenient, expensive and potentially dangerous treatments such as blood transfusions or bone marrow transfers. Today, a better understanding of how cytokines stimulate blood cell production and advances in genetic engineering have enabled the development of new drugs to manage these conditions. Several therapies are in the development pipeline, including the new drugs myelopoietin, promegapoietin and progenipoietin.
The use of genetically engineered cytokines to restore blood cell production after bone marrow suppression has enabled the use of more potent drug regimens to treat cancer. In the case of HIV disease, new antiretroviral therapies -- including protease inhibitors and non-nucleoside reverse transcriptase inhibitors -- are allowing less reliance on the older bone marrow suppressing nucleoside analog drugs. Perhaps in the future, new classes of anti-HIV drugs will be able to control HIV with even fewer detrimental blood-related side effects.
Liz Highleyman is Assistant Editor of BETA.
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