Scientists as well as clinicians have been intrigued by the unusual variety of responses that recipients may demonstrate when challenged with transfused blood products. These responses range from recognizing antigens expressed on transfused blood cells as “foreign” with resultant alloantibody formation to so-called “immunomodulatory” effects whereby the recipient's immune system is actually down-regulated following a transfusion. Examples of the allostimulatory effects of transfusions are the 30% to 60% of patients who develop alloimmunization following platelet transfusions(1) or the high incidence of marrow graft rejection in patients with aplastic anemia who have received blood transfusions prior to marrow grafting.(2) Conversely, immunomodulatory effects have been observed when prior blood transfusions are given before kidney transplantation leading to a higher rate of graft acceptance.(3-5) In addition, based on some published studies, there is now substantial concern that transfusions in the peri-operative period may result in immunosuppression resulting in a higher incidence of post-operative infections(6-7) or higher rates of tumor recurrence/metastasis in cancer patients undergoing potentially curative resections.(8) However, there is a great deal of controversy over whether the clinical trials performed to date have clearly demonstrated that there are transfusion-related immunomodulatory effects leading to these adverse post-operative events.(9) Importantly, there is substantial agreement about one issue: contaminating white blood cells (WBCs) in transfused blood products are intriguingly associated with both the allostimulatory as well as the immunomodulatory effects of transfusion.(10,11) Although the available data suggest that just a quantitative reduction in the number of transfused WBCs may be sufficient to abrogate both the allostimulatory as well as the immunomodulatory effects of transfusions, this is very likely an overly simplistic solution to what may be an extremely complex situation. In fact, a recent study in a mouse transfusion model showed that markedly leukoreduced platelet transfusions were more allostimulatory than those that were less leukoreduced. This effect was associated with the number of transfused B cells.(12) A substantial amount of information is available on the effects of WBC contamination on platelet alloimmunization rates in both man and animal models. As platelet transfusion therapy is lifesaving for many thrombocytopenic patients, the ability to transfuse platelets for an extended period of time until marrow recovery occurs is essential for the care of most cancer patients as well as other patients with dysfunctional marrows; e.g., patients with aplasia or myelodysplasia. However, long-term platelet transfusion therapy often results in platelet alloimmunization in as many as 30%-60% of chronically-transfused cancer patients in spite of them receiving potentially immunosuppressive chemotherapy.(1) With the onset of alloimmunization, most patients become refractory to platelet transfusions from random donors and require HLA-compatible platelet transfusions to maintain hemostasis.(13-15) However, because of the complexity of the HLA system, finding HLA-compatible donors is not always possible.(16) In order to decrease the rates of platelet alloimmunization, efforts have been directed at modifying donor platelets prior to transfusion to reduce their immunogenicity. Animal experiments first suggested that decreasing the number of leukocytes that contaminate the transsfused platelets would lower alloimmunization rates.(17,18) The hypothesis was that immunization requires the transfusion of cells that express both Class I and II HLA antigens; i.e., leukocytes.(19) In contrast, platelets which only express HLA Class I antigens may not only bc non-immunogenic but may even be tolerogenic.(20) How extensive must the leukoreduction be to prevent alloimmunization and what types of WBC need to be removed? A blood product containing <5×106 WBC is considered non-immunogenic by the Food and Drug Administration (FDA).(21,22) More recently, the FDA has suggested <5×106 WBC/transfusions should be the standard to conform to European guidelines. As previously noted, there are even some mouse experiments that suggest extremely leukoreduced blood products are, in fact, more immunogenic than products with less leukoreduction.12 Furthermore, the type of WBC remaining after filtration may vary widely among commercially-available filters and with other leukoreduction porcesses such as platelet apheresis proccdures.(23,24) Therefore, additional studies are needed to determine the amount of leukoreduction required to prevent rather than conceivably enhance alloimmunization and whether immunization is ralated to the types (s) of residual WBC transfused. Using the current leukoreduction guidelines, several prospective, randomized clinical trials have almost uniformly shown a statistically-significant reduction in alloimmunization rates using leukoreduced compared to standard platelet tranfusions (Table1).(25,30) However, the acual effectiveness of the current methods of leukoreduction to prevent platelet alloimmunization may very well be dependent on the immunocompetence of the patients, all the other prevention of platelet alloimmunization transfusion trial that have evaluated leukoreduced blood products have been confined to patients receiving induction chemotherapy for AML.(25-28,30) Interestingly, Williamson etal.(29) did not demonstrate a statistically significant benefit of leukoreduction in patients with solid tumors receiving chemotherapy (although a trend was noted). Benefit was shown only in the subset of patients with AML receiving induction chemotherapy, similar to the results of the other trails. Thus, whether our current mothods of leukoreduction will be proven effective in reducing platelet alloimmunization rates in patients who may bc receiving potentially less or no immunosuppressive therapy - as in cancer patients with solid tumors or in patients with aplastic anemia or myelodysplasia, respectively - remains to be determined.(31) Further evidence that our present methods of preventing platelet allimmunization may not be uniformly effective comes from data obtained during the TRAP Trial.(30) In this large multi-institutional study that enrolled only patients with AML receiving induction chemotherapy (i.e., a potentially very immunosuppressed patient populaton), the underlying rate of immunization in patients who receiving leukoreduced platelets was still 18%. This rate remained even in a small subgroup of the TRAP Trial patients who had no prior antigen exposure by pregnancy or transfusion and whose blood components were all documented to contain the study required <5×106 WBC/transfusion. Efforts to reduce the immunogenicity of platelet transfusions have assumed that it was sufficient to eliminate direct sensitization, i.e. stimulation of recipient CD4-positive T-cells by donor MHC Class II positive cells. Thus, leukocyte-depletion allows acceptance of transfused platelets by a mechanism of immunological ignorance of donor MHC antigens. Indirect sensitization, i.e. presentation of processed donor MHC Class I peptides by host antigen presenting cells was discounted. However, this dogma has been cahllenged by data from a murine model showing that removal of contaminating leukocytes from platelet transfusion products resulted not in ignorance but in sensitization while transfusion of low numbers of leukocytes resulted in tolerance.(12) These data argue that indirect sensitization can lead to refractoriness to platelet transfusion and suggest that leukocytes can down-regulate sensitization. Transfusion of donor leukocytes from blood32 or bone marrow33 has been used to reduce responses to donor MHC in recipients of organ allografts. The goal has been to induce a state of tolerance to donor MHC antigens that would allow acceptance of donor tissue without the need for continued immunosuppression. Tolerance has been shown to be characterized by deletion of alloreactive T-cells or by deviation of T-cell response to subsets producing antiinflammatory cytokines.(34-36) Regulatory cells of donor or host origin have been identified in operationally tolerant hosts which induce apoptosis or anergy in host T-cells responding to donor alloantigens.(37-38) Although donor leukocytes are required for the induction of tolerance, the requirement for donor microchimerism or persistence of donor leukocytes in maintaining tolerance is controversial. (39) (Immunization versus Tolerization) Using a dog platelet transfusion model, we have made some unique observations that may explain how transfusions might be simultaneously allostimulatory and immunomodulatory. Normal immunocompetent recipient dogs received only one type of radiochromium-labeled standard or modified platelets from a randomly-selected initial donor for up to 8 weekly transfusions or until the onset of platelet refractoriness (defined as <5% of the donor dog's platelets circulating in the recipient at 20 hours after two sequential transfusions). Briefly, substantial leukoreduction can be achieved with either filtration (F-LR) or centrifuge leukoreduction (C-LR) procedures. However, prevention of alloimmune platelet refractoriness is achieved in only 31% and 14% of the transfused recipients given these leukoreduced products, respectively (Table 2). Surprisingly, if the two methods of leukoreduction are combined (F-LR/C-LR), then 95% of the recipients are protected from alloimmunization. Furthermore, when non-refractory recipients of C-LR/F-LR platelets were subsequently challenged with up to 8 weekly transfusions of standard (unmodified) platelets from either the initial donor of the treated platelets or even other random donors that the recipient had never previously received, a high rate of tolerance was observed. However, if the donor's F-LR/C-LR platelets are also γ-irradiated before transfusion, subsequent transfusions of standard platelets from the same or third-party donors are not accepted. Our preliminary conclusions from these studies are summarized as follows: Filtration and centrifuge leukoreduction procedures remove different types of allostimulatory WBCs. Both filtration and centrifuge leukoreduction procedures are required to prevent the development of alloimmune platelet refractoriness. After the combined F-LR/C-LR procedures, a residual cell remains that - following repeated transfusions - induces tolerance. Standard platelet transfusions are accepted following a course of F-LR/C-LR platelets, even though they contain high numbers of residual WBCs. Ordinarily, such non-leukoreduced transfusions are highly immunogenic. Tolerance is more likely to be induced to standard platelet transfusions from the “initial” donor of the modified platelets than from “other” donors. As γ-irradiation abrogates tolerance, this suggests that the cell that induces tolerance must be able to divide and replicate in the transfused recipient; i.e., microchimerism has occurred.
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Sherrill J. Slichter (2002) studied this question.
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