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From leukocyte reduction to leukocyte transfusion: the immunological effects of transfused leukocytes.

In transfusion medicine, mononuclear leukocytes have been studied more often as contaminants of red blood cells or platelets responsible for adverse transfusion outcomes than as therapeutic cells; leukocyte transfusion has been effective in augmenting recipient immunity only in limited clinical situations. Studies in leukocyte reduction and leukocyte transfusion have progressed separately as if the leukocytes' adverse and therapeutic effects result from different immunological mechanisms. With growing clinical experience, however, it is increasingly clear that some adverse immune effects may be exploited for therapeutic benefit. Advances in clinical immunology, understanding of the variety of cells and functions in the leukocyte fraction of blood, and blood component preparation technology may lead to new ways of deriving immunological benefit from transfused blood leukocytes while minimizing their adverse effects. This chapter reviews the current uses of leukocyte reduction and mononuclear leukocyte transfusion, with an emphasis on the relationship between transfusion-associated graft-versus-host disease and donor lymphocyte infusion in controlling relapsed leukaemias.

Antigen-Presenting Cells↗

[Approaches to the immunological problems of leukocyte transfusions].

51 leukocyte transfusions from healthy donors and 3 from chronic myelogenous leukemia were given to 16 patients with acute leukemia and 4 with aplasia. During 14 transfusions we have observed clinicals reactions which are of immunological origin. The part of the transfusions and of the pregnancies in the presence of antibodies is argued. The necessity of utilisation of HL-A compatible donors during leukocyte transfusions is asserted.

Blood Donors↗

Reinduction of remission of chronic myeloid leukemia by donor leukocyte transfusion following relapse after bone marrow transplantation: recovery complicated by initial pancytopenia and late dermatomyositis.

A significant proportion of patients relapse after allogeneic BMT for CML. These relapses have been treated by induction of a graft-versus-leukemia effect by transfusing donor leukocytes. We have treated a 27-year-old woman with interferon and donor leukocyte transfusion and a complete haematological and cytogenetic remission was obtained coincident with the onset of GVHD. Her course was complicated by prolonged and profound pancytopenia which was fully reversed by the administration of rGM-CSF. She remains in CR with mild dermatomyositis due to chronic GVHD 17 months after the procedure.

Adult↗

The cost effectiveness of therapeutic and prophylactic leukocyte transfusion.

We analyzed the cost effectiveness of leukocyte transfusion in preventing death from infection during intensive chemotherapy for acute leukemia. Effectiveness was estimated with an odds-ratio analysis based on published results of controlled studies of therapeutic and prophylactic leukocyte transfusion. Cost estimates were based on blood-bank charges throughout the country. Calculations of effectiveness suggest that leukocyte transfusion might prevent 50 to 75% of early deaths from infection. Therapeutic transfusion would add approximately 10.9% to the hospital bill of the average bill of the average leukemic patient and cost $17.7 million annually nationwide. Prophylactic transfusion would add 35.2% to the hospital bill and cost $57.8 million annually. Mean cost-effectiveness ratios were $14,982 per life-year for therapeutic transfusion and $35,020 to $50,029 per life-year for prophylactic transfusion. The cost per additional life-year achieved with prophylactic rather than therapeutic leukocyte transfusion was $85,291. These data suggest that leukocyte transfusion is an extremely expensive technologic procedure.

Acute Disease↗

Cytomegalovirus infections associated with leukocyte transfusions.

Patients randomized to receive or not to receive prophylactic leukocyte transfusions were evaluated prospectively for serologic, histologic, and cultural evidence of cytomegalovirus infection. Recipients of prophylactic leukocyte transfusions and control subjects were similar with regard to age, sex, underlying disease, immunosuppressive therapy, and number of other transfusions. The recipients of prophylactic leukocyte transfusions (mean, 23.1) had significantly more cytomegalovirus infections (19 of 31 versus seven of 27, p = 0.01) than did control patients receiving no leukocytes or only therapeutic leukocyte transfusions (mean, 3.8). Twenty-seven of 66 donors of leukocytes were seropositive for cytomegalovirus complement-fixation antibody, but cytomegalovirus was not isolated from any of 62 leukocyte transfusions cultured for virus. These results are consistent with the hypothesis that latent cytomegalovirus may be present in leukocytes of blood donors with previous cytomegalovirus infection and after transfusion may be activated to produce active cytomegalovirus infection.

Adolescent↗

[Leukocyte transfusion in complex treatment of acute pulmonary suppurations].

The authors studied the effect of transfusions of a leukocyte suspension on the main clinico-immunological values of homeostasis in 56 patients with acute pyodestructive diseases of the lungs. They found that inclusion of leukocyte transfusions in the complex of therapeutic measures produced a marked clinical effect, reduced the term of treatment, and allowed successful control of endotoxicosis and immunodeficiency in patients with pulmonary suppuration. Immune leukocytes obtained according to a specially developed method had a more marked immunocorrective effect.

Acute Disease↗

Characteristics and natural history of alloimmunization following HLA-matched leukocyte transfusion in Hunter's syndrome.

The characteristics and natural history of alloimmunization to HLA were studied in five patients with Hunter's syndrome receiving long term transfusions of leukocytes collected from human leukocyte antigen (HLA) matched donors. Patients were not given any other blood component transfusions. All patients became alloimmunized at an average interval of eight months following an average of 15 transfusions. All patients developed HLA alloantibodies to transfused cross-reactive HLA antigens. Antibodies to transfused incompatible HLA antigens also developed in all patients. Multispecific HLA antibodies in which specificity determination could not be made were also seen in four patients. In a small number of patients in this study, despite matching for the private HLA specificities, HLA alloimmunization was not prevented. In fact, broad alloimmunization was seen uniformly in our patients.

Adult↗

Symposium on infectious complications of neoplastic disease (Part II). Leukocyte transfusions: thinking twice.

There is convincing evidence that leukocyte transfusions have a definite, albeit restricted, role in managing profoundly neutropenic patients and certain rare patients with qualitative disorders of neutrophil function. Nonetheless, leukocyte transfusion techniques have yet to meet a number of important conceptual challenges of neutrophil replacement. Even with pharmacologic manipulation of leukocyte donors, current methods of leukapheresis cannot provide neutrophils in numbers that match the body's normal use and turn-over of these cells. Neutrophils have also proved to be fragile cells in the blood bank, readily losing normal function with certain collection procedures and during short periods of storage. Moreover, transfused neutrophils that are unable to function and circulate normally in recipients can produce serious toxic reactions. In light of the marginal demonstrable benefits of leukocyte transfusions, potential toxicity is necessarily an important consideration in decisions to use this form of hematologic support. The fact that leukocyte recipients are usually extremely ill does not alter the physician's responsibility to avoid bringing harm to the patient without benefit.

Adult↗

Leukocyte transfusions for the prophylaxis and treatment of infections associated with granulocytopenia.

The role of leukocyte transfusions in the prevention and treatment of infections in adults with granulocytopenia was investigated. Leukocytes were obtained from healthy volunteers by continuous-flow centrifugation. Histocompatibility antigen (HLA)-matched leukocytes were used to assess the prophylactic value of leukocyte transfusions. Seven patients with acute myelogenous leukemia received HLA-matched leukocytes during the period of maximal granulocytopenia associated with initial remission induction therapy; 20 concurrently treated patients who did not receive leukocyte transfusions were the control group. The patients receiving HLA-matched leukocytes had significantly fewer (P = 0.043) infectious episodes (not bacteriologically proven) during the study period, and remission occurred in 5 of the 7, compared with 10 of the 20 controls. In addition, 52 series of two or more ABO-compatible transfusions were given to 50 patients with proven infection or elevated temperature presumed due to infection and a granulocyte count of less than 0.5 X 10(9)/L. Response, indicated by a decrease in temperature, occurred in 23 patients. Leukocyte transfusions thus have an important adjuvant role in the management of patients with severe granulocytopenia.

Adolescent↗

Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions.

Amphotericin B is used increasingly in high-risk patients with profound neutropenia and suspected sepsis. We have observed serious pulmonary reactions characterized by acute dyspnea, hypoxemia, and interstitial infiltrates on chest films in patients receiving amphotericin B and leukocyte transfusions. We reviewed 6 1/2 years of experience at the National Institutes of Health to determine whether this combination was associated with pulmonary toxicity not characteristic of either therapy alone. Amphotericin was used during 22 of 57 leukocyte-transfusion courses. Acute respiratory deterioration occurred during 14 (64 per cent) of these courses but in only two (6 per cent) of 35 courses without amphotericin (P less than 0.01). In seven cases, respiratory deterioration began during or immediately after amphotericin infusion, and it contributed to death in five patients. Diffuse intraalveolar hemorrhage was found when lung biopsy or autopsy was performed. Acute respiratory deterioration was not observed in comparably neutropenic patients given amphotericin but not leukocyte transfusions during the same period. It was mot common when amphotericin was begun with or after institution of daily leukocyte transfusions. Leukocyte transfusions may cause changes in the lungs that amplify the acute toxicity of amphotericin, thereby permitting severe pulmonary reactions.

Adolescent↗

[Immunological effects of erythrocyte and leukocyte transfusion. Work Group Blood Group Serology of the Medical Advisory Commission of the College for Blood Transfusion of the Netherlands Red Cross].

Immunological consequences of blood transfusion are less well-known than infectious complications although they occur more frequently. In many cases the effects in individual patients are hardly visible although fatal transfusion reactions may occur: Transfusion of red cells may induce acute or delayed haemolytic transfusion reactions. Transfusion of leukocytes may suppress the function of the immune system of the recipient (with consequences for immune tolerance in transplant patients, cancer surveillance and the occurrence of postoperative infections) but also may induce graft versus host disease.

Erythrocyte Transfusion↗

[Therapeutic effect of donor leukocyte transfusion in relapsing marrow transplants in Japan].

The immune reactivity of allogeneic lymphocytes plays a major role in control of leukemia after bone marrow transplantation. We studies the efficacy of donor leukocyte transfusion (DLT) on acute and chronic leukemia in relapse after bone marrow transplantation in Japan. Sixty nine patients with chronic myelocytic leukemia (N = 17), acute lymphoblastic leukemia (N = 25), acute myelocytic leukemia (N = 26), myelodysplastic syndrome (N = 5), non-Hodgkin lymphoma (N = 2) and rhabdomyosarcoma (N = 1) were treated with transfusions of donor lymphocytes. Therapeutic effects were induced by donor leukocyte transfusion in 20 patients (29%) including 3 patients out of 4 (75%) with CML in cytogenetic and chronic phase relapse, 4 out of 5 (80%) patients with myelodysplastic syndrome, 3 out of 13 (23%) patients with CML in transformed phase, 5 out of 25 (20%) patients with acute myelocytic leukemia, and 4 out of 20 (20%) patients with acute lymphoblasic leukemia. Twenty two patients (30%) developed acute GVHD (> or = 2) and 6 out of 73 (8.2%) patients developed fatal GVHD after donor leukocyte transfusion. Patients relapsed within 6 months after marrow transplantation had a probability of having severe acute GVHD (> or = 2) after DLT. Fourteen out of 24 (58%) patients with GVL response were re-relapsed thereafter. Minimal dose of donor leukocytes infused in successfully treated 9 patients without cytoreductive therapy was 2 x 10(7)/kg in total and minimal dose of that in 6 patients with fatal GVHD was 7 x 10(7)/kg in total. The anti-leukemia effect of donor leukocyte transfusion was strongest against CML in cytogenetic and chronic phase and induce a durable complete remission.

Adolescent↗

Improved survival of newborns receiving leukocyte transfusions for sepsis.

To determine the role of polymorphonuclear (PMN) leukocyte transfusions in neonates with sepsis, 23 consecutive newborns were prospectively randomly selected during an 18-month period in a treatment plan to receive polymorphonuclear leukocyte transfusions with supportive care or supportive care alone. Thirteen neonates received transfusions every 12 hours for a total of five transfusions. Each transfusion consisting of 15 mL/kg of polymorphonuclear leukocytes was subjected to 1,500 rads of radiation. The polymorphonuclear leukocytes were obtained by continuous-flow centrifugation leukapheresis and contained 0.5 to 1.0 X 10(9) granulocytes per 15 mL with less than 10% lymphocytes. Pretreatment demographic, clinical, and laboratory variables that were found to be insignificant in prognosis between newborns who received transfusions and newborns who did not receive transfusions included weight, gestational and postnatal age, hypoxia, acidosis, hypotension, initial absolute granulocyte count (AGC), initial levels of immunoglobulins (IgA, IgG, and IgM), and total hemolytic complement. Positive findings on blood cultures were obtained in 14/23 patients and seven were randomly selected for each treatment group. Absolute granulocyte counts were less than 1,500/microL in 13 patients but tibial bone marrow examinations revealed that the neutrophil supply pool was depleted in only three patients. The survival was significantly greater in the treatment group (13/13, 100%) compared with the group that did not receive transfusions (6/10, 60%, P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Infections↗

The role of ultraviolet B-irradiated leukocyte transfusions and cyclosporine in intestinal transplantation.

To explore the efficacy of ultraviolet B-irradiated donor-specific leukocyte transfusions (UV-DSLT) with short-term cyclosporine to control intestinal allograft rejection, 75 adult Lewis (RT1l) rats underwent total small-intestinal transplantation from Brown-Norway (RT1n) donors. Recipients were randomly divided into ten treatment and control groups utilizing various combinations of donor-specific and third-party (Wistar-Furth, RT1u) leukocyte transfusions (TPLT), with or without transfusion UVB irradiation, and either alone or in combination with short-term cyclosporine administration (5 mg/kg intramuscularly on days -7, 0, 1, and 2 relative to transplantation). Leukocytes (10(8) cells) separated from a spleen cell suspension were infused on day -7. Certain transfused leukocytes were treated with 12,000 joules/m2 of UVB irradiation. Groups were monitored for mean survival time (MST) and cause of death. UV-DSLT alone (MST = 19.8 +/- 4.6) or in combination with cyclosporine (UV-DSLT+CsA, MST = 53.1 +/- 22.5) significantly (P less than 0.003-0.0002, Mantel-Cox) prolonged recipient survival when compared with appropriate controls (i.e., no treatment, MST = 11.2 +/- 3.4; CsA, MST = 17.2 +/- 9.0; UV-TPLT, MST = 12.4 +/- 4.0; and UV-TPLT+CsA, MST = 25.1 +/- 9.7) No significant increase in graft-versus-host disease occurred in any group, with 85% (64/75) of the recipients dying of acute rejection. Conversely, the UV-DSLT+CsA group had a significant increase (9/11; chi-square, P less than 0.0001) in chronic rejection. Because UV-DSLT+CsA improved survival as compared with third-party controls, a limited donor-specific unresponsiveness may have been induced. Furthermore, this treatment produces a consistent, chronic rejection rodent intestinal allograft model.

Animals↗