Anemia in the elderly. Symptoms, causes, and therapies

Anemia is common in the elderly, but it is not a normal manifestation of aging and should be evaluated as it would be in a younger person. History taking, physical examination, assessment of red cell morphology, and simple laboratory evaluations (ie, reticulocyte count, iron studies, vitamin levels, sometimes bone marrow examination) usually elucidate the cause. Hypoproliferation of red cells is the most common form of anemia in the elderly, caused more often by chronic disease or iron deficiency and less often by vitamin deficiencies or bone marrow infiltration. Anemia with an elevated reticulocyte count, seen less often in the elderly, suggests acute blood loss or hemolysis. In some patients, the cause is not obvious, and anemia is likely due to increased sensitivity of the hematopoietic system to multiple insults and decreased homeostatic reserve. Transfusions should be used judiciously in patients with symptomatic anemia who are likely to benefit from increased oxygen delivery after transfusion.     

失血性贫血小鼠骨髓间充质干细胞向成骨成脂分化的变化简

本研究旨在检测骨髓间充质干细胞（multipotent mesenchymal stem cells,MSC）向成骨、成脂分化的变化,探讨骨髓间充质干细胞的分化状态对骨髓造血功能的影响.先对实验小鼠每隔1-2d行内眦静脉取血0.3 ml,4周构建贫血模型,通过检测贫血小鼠外周血常规指标、网织红细胞比例、骨髓细胞造血集落形成以验证小鼠模型.通过检测贫血模型小鼠成纤维细胞集落形成、骨髓细胞和脂肪细胞的数量,并用实时定量PCR的方法检测骨髓成骨、成脂分化相关基因的表达来研究骨髓MSC分化潜能的改变.结果显示,与对照组相比,贫血小鼠红细胞数量和血红蛋白水平明显下降,网织红细胞比例增高,骨髓细胞造血集落形成单位数量增多;骨髓造血细胞增多,脂肪细胞减少;骨髓成纤维细胞集落形成单位增多并显著向成骨细胞分化;骨髓成骨分化相关基因Runx2和OSX的表达明显升高,而成脂相关基因aP2、PPARγ2的表达明显降低.结论：在骨髓造血功能活跃期小鼠骨髓间充质干细胞向成骨细胞分化能力增强,向脂肪细胞分化能力减弱.     

TOOTH GROWTH IN EXPERIMENTAL SCURVY

1. The incisor teeth of guinea pigs have a constant rate of growth in health. 2. Deprivation of Vitamin C causes the teeth to cease growing. Readministration of the vitamin restores the growth. 3. Administration of small amounts of antiscorbutic substance results in rates of growth roughly proportional to dosage. 4. Under standard experimental conditions used in the testing of foodstuffs for antiscorbutic value, the rate of tooth growth would appear to be a precise indication of the degree of scurvy, being more delicate than the Sherman score, and more constant as well as more simple, than the Höjer method. 5. Stress in terms of usage appears to exaggerate the scorbutic lesions in the teeth.     

THE EFFECTS OF EXPERIMENTAL PLETHORA ON BLOOD PRODUCTION

With the purpose of determining whether a diminished activity of the bone marrow could be brought about experimentally, plethora was produced in rabbits by means of repeated small transfusions of blood. Counts of the number of reticulated red cells in the circulating blood were made during the course of the experiments as an index to changes in the activity of the bone marrow. With the development of plethora, the number of reticulated cells in the blood decreased. In the majority of the plethoric animals, this diminution was extreme, and in some instances, reticulated cells practically disappeared from the blood. A comparison of the red bone marrow of these animals with that of normal controls revealed a marked reduction in the content of reticulated cells. After a number of transfusions, there occurred in some of the plethoric rabbits a sudden and marked drop in hemoglobin. The hemoglobin continued to fall until a severe grade of anemia was reached. This was followed by an extremely rapid regeneration accompanied by a striking rise in color index. During regeneration, the reticulated cells were enormously increased in number. Taken together, these facts show that the bone marrow is markedly influenced by plethora. The diminished number of reticulated cells observed, both in the circulating blood and in the marrow, would make it appear that a decided decrease in blood production occurs. The reduction in the number of these cells cannot be due to changes in the constitution of the red cells put out by the bone marrow, as a result of an increased quantity of hemoglobin in the body, because during regeneration from the above mentioned anemia, when the color index was very high, reticulated cells were still present in large numbers. That the activity of the bone marrow does actually diminish during plethora is further evidenced by the occurrence of the anemia. The most reasonable explanation of this phenomenon is that the recipient develops an immunity against the blood of the donors, which results in the destruction of the strange cells that are in circulation. In keeping with this conception is the appearance of isoagglutinins for the donors'' red cells in the blood of the recipient, at about the time of the beginning fall in hemoglobin. The occurrence of anemia as a result of the destruction of the alien blood only would seem to be due to the circumstance that, during the period of plethora, blood production is greatly diminished; as a consequence, the blood cells proper to the recipient are gradually reduced in number and replaced by alien cells until the latter come to constitute the bulk of the animal''s blood. In those rabbits developing anemia, the initial drop of hemoglobin from the plethoric level to the normal was constantly accompanied by a marked rise in the number of reticulated cells. This brought up a subsidiary problem for study. With the idea that the stimulation of the bone marrow might be due to the presence of an increased quantity of broken down blood, rabbits, were injected intravenously with large amounts of laked blood cells. The procedure had no evident effect on the blood picture. It was then found that simple blood removal from a plethoric animal which brought back the hemoglobin to the normal level, or even to a point somewhat above, sufficed to cause a marked increase in the number of reticulated cells. Although these findings are not conclusive, they suggest an explanation for the increased bone marrow activity accompanying the initial drop of hemoglobin in the plethoric rabbits; namely, that the organism had in some way adapted itself during the period of plethora to the presence of a greater amount of blood and that the result of blood loss in such an organism was a relative but not absolute anemia. The finding that the activity of the bone marrow can be depressed by the introduction of a large quantity of blood into the circulation accounts for the diminished bone marrow activity which sometimes occurs after transfusion in pernicious anemia. In such cases there is a marked drop in the number of reticulated cells and other evidence of bone marrow depression; the patient shows no benefit from transfusion or may grow rapidly worse. The cause of this depression is best explained on the basis that in severe instances of the disease where exhaustion of the bone marrow is imminent, the stimulus of the anemia is only just sufficient to keep the marrow functioning. A sudden lowering of this stimulus is brought about by the introduction of a large quantity of blood into the circulation, and the result is a fall in the activity of the bone marrow. It follows from this that in pernicious anemia with a feebly reacting bone marrow as indicated by the number of reticulated red cells, small transfusions are preferable to large ones.     

Pathophysiology, diagnosis and treatment of anemia

Anemia can result from deficient erythropoiesis [aplastic anemia, myelodysplastic syndromes (MDS), iron deficiency anemia, anemia of chronic disease (ACD), thalassemia, megaloblastic anemia, chronic renal failure, hematological malignancies, etc.], excessive RBC destruction [hereditary spherocytosis, inherited enzyme deficiency, hemoglobinopathies, autoimmune hemolytic anemia (AIHA), paroxysmal nocturnal hemoglobinuria (PNH), etc.], and blood loss. Based on the measured red cell size(MCV), anemia is classified as microcytic, normocytic, or macrocytic. Iron parameters (serum iron, serum ferritin, etc.), reticulocyte count, bone marrow examination, Coombs test, serum vitamin B12 level, and Ham test are also useful in the differential diagnosis of anemia. Novel treatment of anemia includes lenalidomide for 5q(-)MDS, azacitidine for high-risk MDS, and eculizumab for PNH. Oral iron chelator(deferasirox) developed for the treatment of transfusional iron overload is also very useful for the management of patients with bone marrow failure syndromes.     

HISTOLOGICAL STUDIES OF THE BONE MARROW IN FASTED AND POLYNEURITIC PIGEONS

1. The histological changes of the bone marrow in fasted and rice disease pigeons are essentially the same. 2. The histological changes of the bone marrow in pure vitamin B deficiency consist of degeneration and edema and slight endothelial proliferation of the small vascular channels, but with active hematopoiesis. 3. The anemia of rice disease in pigeons is in large part a starvation anemia and not directly related to vitamin B deficiency.     

A three-point approach to anemia

Anemia is a sign of underlying disease that is causing blood loss, sequestration of red blood cells (RBCs), impaired RBC production, or primary marrow dysfunction. The most efficient clinical approach to a patient with anemia is to ask the following three questions: Is the anemia microcytic, macrocytic, or normocytic? Is pancytopenia present? Is the marrow response appropriate for the anemia as determined by the reticulocyte count? Answers to these questions focus laboratory evaluation on a logical progression and avoid a costly shotgun approach.     

The effect of smoking on the composition of the peripheral blood in normal subjects]

The peripheral blood erythrocytic and leukocytic status was studied in 60 healthy young tobacco-smokers and in 30 non-smokers. The smokers were divided into two subgroups, each with 30 members: those smoking for not more than 5 years and those smoking for 6 to 10 years. A trend to inhibition of erythro- and leukocytopoiesis was detected in Subgroup 1 tobacco smokers: reticulocyte maturation rate was reduced, as was bone marrow production and the level of circulating red cells, macrocyte count was increased and planocytosis was likely to develop, leukocyte counts were decreased at the expense of the neutrophils, eosinophils, and monocytes; basophil count was growing. Subgroup 2 tobacco-smokers presented with normalization of erythro- and leukocytopoiesis: reticulocyte maturation rate was growing, as was bone marrow production and the count of circulating red cells, erythrocytogram normalized, leukocyte count was increasing at the expense of the neutrophils, eosinophils, and lymphocytes; basophil count has decreased. The detected changes in the peripheral blood erythro- and leukocytic composition, related to the duration of tobacco-smoking, appear to reflect different phases of tobacco smoke toxic product effects on the bone marrow and the formation of the defense, adaptive, allergic, and immunologic reactions of the body in conditions of prolonged tobacco antigenemia.     

An unusual case of autoimmune hemolytic anemia with reticulocytopenia, erythroid dysplasia, and an IgG2 autoanti-U

BACKGROUND: Autoantibodies with anti-U specificity, usually in combination with autoantibodies of other specificities, have occasionally been identified in association with autoimmune hemolytic anemia. A case of life-threatening autoimmune hemolytic anemia, characterized by several atypical features, including apparent intravascular hemolysis associated with an IgG2 anti-U, reticulocytopenia, and bone marrow dyserythropoiesis is described. CASE REPORT: A 36-year-old man with a severe case of acute-onset autoimmune hemolytic anemia was admitted to another hospital; he had a hematocrit of 15 percent, elevated bilirubin and lactate dehydrogenase, and positive direct and indirect antiglobulin tests. He received 7 units of incompatible red cells without improvement in hematocrit, and he was transferred to University Hospitals of Cleveland (OH). He was jaundiced and became syncopal in the sitting position. His serum was reddish pink; he had a hematocrit of 11.8 percent and a reticulocyte count of 2.5 percent. No spherocytes were observed in the peripheral blood smear. Shortly after admission, the hematocrit fell to 6.9 percent. He was given 3 units of “least-incompatible” red cells and was started on prednisone, with little improvement. An IgG2 autoanti-U was detected in his serum. Seven units of U- red cells were transfused over the next 4 days. The hematocrit improved to 23 percent and continued to rise without further transfusion. A bone marrow examination, initially revealing erythroid hyperplasia accompanied by dyserythropoiesis, became morphologically normal. Drug studies failed to show evidence of drug-related hemolysis. He remains well 2 years after discharge without evidence of recurrent hemolysis. CONCLUSION: Severe life-threatening autoimmune hemolytic anemia, in this instance induced by an autoanti-U, may be associated with IgG2 autoantibody and characterized by apparent intravascular hemolysis and bone marrow dyserythropoiesis. Early treatment with U- blood, in addition to steroids, may be beneficial.     

Serum transferrin receptor is a marker of iron deficiency in patients included in programs for preoperative autologous blood donation.

Recently programs for preoperative autologous blood donation (PABD) have expanded to reduce the need for allogenic blood transfusion. Nevertheless, the ability of the patients's bone marrow to replace the red blood cells (RBCs) mass reduced by phlebotomies determines the efficacy of PABD. In mild anemia, known as iron-deficient erythropoiesis (IDE) or iron deficiency without anemia, precipitated by PABD, the marrow response is suboptimal and needs adjuvant therapy. The aim of this study was to evaluate the use of the serum transferrin receptor (sTfR) for the assessment of IDE in patients undergoing PABD. METHODS: Two autologous blood units from 50 consecutive patients scheduled for elective orthopedic surgery were collected preoperatively. Serial measurements of RBCs, haematocrit (Hct), haemoglobin (Hb), serum iron, serum ferritin, reticulocyte count, reticulocyte maturity index (RMI), endogenous erythropoietin (EPO) and sTfR were performed throughout the phlebotomy program. RESULTS: RBC, Hct, Hb and serum iron significantly decreased although within the normal range. There was no change in serum ferritin levels. Reticulocytes, RMI and EPO significantly increased as did sTfR which significantly exceeds the normal range. CONCLUSIONS: These results demonstrate that the sTfR is a reliable laboratory marker for detecting mild anemia or IDE. In patients undergoing PABD increased sTfR levels may suggest a treatment with recombinant human EPO (rh-EPO) or iron to improve the bone marrow performance.     

THE NORMAL FATE OF ERYTHROCYTES : II. BLOOD DESTRUCTION IN PLETHORIC ANIMALS AND IN ANIMALS WITH A SIMPLE ANEMIA.

1. The increased destruction of red cells in animals rendered plethoric by transfusion takes place predominantly by a fragmentation of the corpuscles without loss of hemoglobin. 2. The microcytes and poikilocytes observed in animals with a severe anemia due to hemorrhage are not put forth as such by the bone marrow, but are portions of cells fragmented while circulating. 3. The cells thus fragmented are for the most part those newformed to meet the exigencies of the situation. Such cells are in large part unable to withstand the wear and tear of function. There results a vicious circle. The anemia renders the bone marrow unable to put forth proper cells, and those it does produce are soon destroyed, thus prolonging the condition. A similar state of affairs probably exists in many human anemias. 4. The occurrence of large accumulations of microcytes and poikilocytes in the spleen of anemic and plethoric animals indicates that the organ exercises some important function in connection with these forms. The same is true of normal animals, for the findings in them are similar, though less striking. 5. The normal fate of the red corpuscles, in those species in which phagocytosis is negligible, is to be fragmented one by one, while still circulating, to a fine, hemoglobin-containing dust. The cell fragments are rapidly removed from the blood, but their ultimate fate remains to be determined. The facts indicate that they are removed from the blood by the spleen, and under exceptional conditions, by the bone marrow.     

Reticulocyte count with maturation fractions in pancytopenic evaluation by a fully automated counter

Using a fully automated reticulocyte counter, the roles of the reticulocyte count with maturation in pancytopenia were evaluated. Different groups of pancytopenia including aplastic anemia, infiltrative marrow disorder, hypersplenism, and megaloblastic anemia were recruited. All patients had bone marrow examinations for morphological diagnosis and reticulocyte evaluation using an automated counter. The roles of these parameters were then analyzed statistically in the differential evaluation among these conditions. The following subjects were studied: 292 normal subjects, 67 cases of aplastic anemia, 69 cases of marrow infiltration by different malignancies, 35 cases of hypersplenism, and 13 cases of megaloblastic anemia. The results showed that the absolute retlculocyte counts were lowest in the groups of aplastic anemia and megaloblastic anemia and highest in hypersplenism. Both showed significant differences from the infiltrative groups. The maturation fractions were most immature in the group of marrow infiltration and are significantly different from the other groups. It was concluded that the highest absolute reticulocyte count (>0.09 10¹²/L) obtained in pancytopenic patients suggests it to be a case of hypersplenism. The lowest counts ( < 0.03 10¹²/L) with lowest immature fractions ( < 10%) suggest the groups of aplastic or megaloblastic anemias. The highest immature fractions ( >30%) with a nearly normal reticulocyte count favor the group of marrow infiltration. © 1993 Wiley-Liss, Inc.     

Interleukin-3 in the treatment of myelodysplastic syndromes

Summary Patients with myelodysplastic syndromes frequently present with anemia, leukopenia and thrombocytopenia due to defective maturation of bone marrow cells. Clinical studies with hematopoietic growth factors, including interluekin-3 (IL-3), have been undertaken to evaluate the possibility to reverse cytopenia. In initial phase I/II trials, treatment with IL-3 has resulted in an increase of neutrophil counts in 59%, of platelet counts in 34%, and in reticulocyte counts in 25% of the patients. Adverse effects were rather mild but in individual patients a reversible decrease in platelet counts and in the number of blast cells in blood and bone marrow were observed. Further clinical trials should concentrate on the combination of an early acting cytokine like IL-3 and later acting hemopoietic growth factors like erythropoietin and granulocyte colony-stimulating factor.     

CHANGES IN THE BONE MARROW AND BLOOD CELLS OF DEVELOPING RABBITS

1. The full number of erythroid cells in the blood stream of the rabbit is reached by the 3rd week of life. 2. During this period, there is a predominance of erythrogenesis in the bone marrow. 3. During the 2nd week of life the bone marrow is in a state of hyperplasia owing to the needs of the body for blood and the small space available for the marrow. 4. This hyperplasia is reduced as the growth of the bone permits the marrow to spread. The control of the growth of the bones has an important bearing on hematopoiesis. 5. During the first 3 weeks of life, the chemical factors for the multiplication of red cells as well as for the elaboration of hemoglobin become available. 6. The amount of hemoglobin does not increase as rapidly as the number of cells, so that the macrocytic anemia of the fetus becomes reduced. The proportion of hemoglobin per red cell characteristic of the adult rabbit is reached by the 3rd month. 7. Further evidence on the intravascular origin of red blood cells is given. 8. The development of all of the white blood cells, with the exception of the monocyte, goes on at a slower rate than that of the red cells. 9. The monocytes reach their full number in the blood stream in the 1st week of life; granulocytes and lymphocytes by the 5th and 6th months. 10. Each of the three strains of white cells has a different rate of development. 11. The question as to whether the stem cell or primitive cell is identical with the lymphocyte is discussed.     

Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia

Erythropoiesis in normal man was studied during periods of phlebotomy-induced anemia of varying severity. This study permitted a comparison of marrow production measurements over a wide range of marrow production levels. As long as the serum iron remained above 50 mug/100 ml, measurements of plasma iron turnover provided an excellent index of marrow production at all levels of red cell production. In contrast, the absolute reticulocyte count demonstrated a poor correlation with the other measurements. This was shown to be the result of a prolongation of the time required for circulating reticulocytes to lose their reticulum, which correlated with the severity of the anemia. For the clinical application of the reticulocyte count as a measurement of marrow production, an adjustment must be made for this alteration in the circulating reticulocyte maturation time.     

THE EFFECT OF HYPERTROPHIC CARTILAGE ON BONE MARROW GROWTH

Intravenous injections of colloidal thorium dioxide were made in rabbits and moderate amounts caused no significant changes in the cellular elements of venous blood. Thorium dioxide was held locally with great tenacity in the cells of the reticulo-endothelial system in the bone marrow and showed little tendency to migrate despite drastic stimuli to the marrow in the form of anemia and plethora. In recently injected rabbits, thorium-laden macrophages abutted each cartilage column in the direction of growth where the cartilage was being removed. In marrow which had formed subsequent to injection the macrophages were thorium-free, allowing recognition of the new tissue by x-ray and histological techniques as clear zones. The growth pattern of marrow could be detected in this way. The bone marrow increases in length principally in the region of hypertrophic cartilage at the metaphyses and it is evident that the increase is facilitated by the presence of macrophages whose primary function is the resolution of the wasted hypertrophic cartilage cells. Growth in thickness of bone marrow occurs at its circumference. In contrast to the zonal growth of bone marrow, growth of the reticuloendothelial system in liver and spleen is chiefly interstitial.     

Erythropoiesis in the anemia of bone marrow failure

The quantitative relationship between red cell volume, erythropoietin level, and erythropoiesis was evaluated in 43 human beings. Results in normal man were compared with studies in patients with anemia from bone marrow failure and with polycythemia vera. The maximum erythropoietin excretion after bleeding normal men was similar to the basal levels found in patients with chronic anemia of similar magnitude. Although erythropoietin values were low in patients with polycythemia vera, bleeding evoked a normal response. In patients anemic from bone marrow failure, basal levels were elevated, and phlebotomy resulted in an increase consistent with the new level of anemia. These observations indicate that erythropoietin level is affected primarily by the degree of anemia and is not influenced by the duration of anemia. In normal subjects, a fivefold increase in urinary erythropoietin was associated with a doubling of erythropoiesis. Despite similar degrees of erythropoietin production, anemic patients with evidence of bone marrow in the lower extremities had greater red cell production. In patients with polycythemia vera, red cell production was inappropriately elevated with regard to the urinary erythropoietin excretion. Bone marrow maturation time was not shortened in patients anemic from bone marrow failure to the same degree as in bled, normal volunteers. In addition to an adequate level of erythropoietin production, normal bone marrow function is necessary for maximal shortening of maturation time.     

Interleukin-3 in the treatment of myelodysplastic syndromes.

Patients with myelodysplastic syndromes frequently present with anemia, leukopenia and thrombocytopenia due to defective maturation of bone marrow cells. Clinical studies with hematopoietic growth factors, including interleukin-3 (IL-3), have been undertaken to evaluate the possibility to reverse cytopenia. In initial phase I/II trials, treatment with IL-3 has resulted in an increase of neutrophil counts in 59%, of platelet counts in 34%, and in reticulocyte counts in 25% of the patients. Adverse effects were rather mild but in individual patients a reversible decrease in platelet counts and in the number of blast cells in blood and bone marrow were observed. Further clinical trials should concentrate on the combination of an early acting cytokine like IL-3 and later acting hemopoietic growth factors like erythropoietin and granulocyte colony-stimulating factor.     

LOCAL PROGRESSION WITH SPONTANEOUS REGRESSION OF TUBERCULOSIS IN THE BONE MARROW OF RABBITS,CORRELATED WITH A TRANSITORY ANEMIA AND LEUCOPENIA AFTER INTRAVENOUS INOCULATION

In this series of rabbits it was found that the rabbits dying during the 1st month after an injection of I or 2 mg. of bovine tubercle bacilli show the same conditions: extreme tuberculosis of the lungs, acute splenic tumor with tuberculosis, involvement of the lymph glands, an occasional small tubercle in the liver and extensive tuberculosis of the bone marrow. The peripheral blood has shown a sharp fall in the platelet count, an anemia and a fall in the granulocytic strain of white cells, and these changes have been correlated with the condition of the bone marrow. There has also been a rise in monocytes and a fall in lymphocytes, to a reversal of the normal ratio. When the rabbits have survived the first acute phase of the disease longer than 3 to 4 weeks, there have been signs in the peripheral blood of a recovery of the bone marrow; the first indication of this has been an increase in platelets, then a rise in hemoglobin followed in 1 or 2 days by a rise in red cells and later a return of the three strains of granulocytes. The bone marrow has shown a rapid spontaneous disintegration of the epithelioid cells correlated with the appearance of increased evidence of acid-fast debris in clasmatocytes, especially clear in those that lie along the vessels. The animals that have survived into the 3rd month have all shown a hyperplastic phase of the healing marrow, both the red cells and all types of the granulocytes appearing in the peripheral blood in numbers above the normal. The epithelioid cells originally containing many bacilli all disappear from the marrow and the only sign left, possibly suggestive of the tuberculosis, is the acid-fast granules in the clasmatocytes. Finally, the marrow becomes entirely normal, giving the normal number of red cells and granulocytes to the blood. Thus, bone marrow in the rabbit has become involved in every instance with the injection of massive doses of viable bacilli. The findings at autopsy in those animals followed during the early reaction to infection confirm this directly and, since the curves of the cells in the peripheral blood of the more chronic animals were the same during the early stages of the disease as in those that died, the same conclusion seems justified from indirect inference for them. The method of healing has been a rapid disintegration of the epithelioid cells without caseation. The bone marrow heals itself entirely regardless of the progress of the disease elsewhere, so that one sees the remarkable condition of an animal recovering from the anemia and leucopenia while dying of tuberculosis elsewhere. The spleen also shows a tendency toward spontaneous healing. In the animals that have lived beyond 100 days there has been some gradual lessening of the diffuse distribution and extent of pulmonary lesions with the development of cavitation together with a marked involvement of the kidneys and lesions in the eyes.     

CELLS INVOLVED IN THE IMMUNE RESPONSE : VI. THE IMMUNE RESPONSE TO RED BLOOD CELLS IN IRRADIATED RABBITS AFTER ADMINISTRATION OF NORMAL, PRIMED, OR IMMUNE ALLOGENEIC RABBIT BONE MARROW CELLS

Irradiated rabbits given allogeneic bone marrow cells from normal adult donors responded to an injection of sheep red blood cells by forming circulating antibodies. Their spleen cells were also capable of forming many plaques using the hemolysis in gel technique, and were also capable of undergoing blastogenesis and mitosis and of incorporating tritiated thymidine upon exposure to the specific antigen in vitro. However, irradiated rabbits injected with allogeneic bone marrow obtained from rabbits injected with sheep red blood cells 24 hr prior to sacrifice (primed donors) were incapable of mounting an immune response after stimulation with sheep red cells. This loss of reactivity by the bone marrow from primed donors is specific for the antigen injected, since the immune response of the irradiated recipients to a non-cross-reacting antigen, the horse red blood cell, is unimpaired. Treatment of the bone marrow donors with high-titered specific antiserum to sheep red cells for 24 hr prior to sacrifice did not result in any diminished ability of their bone marrow cells to transfer antibody-forming capacity to sheep red blood cells. The significance of these results, with respect to the origin of the antigen-reactive and antibody-forming cells in the rabbit, is discussed.