Mini Review

Bone Marrow Transplantation (2004) 33, 1–7. doi:10.1038/sj.bmt.1704284 Published online 1 December 2003

Novel processes for inactivation of leukocytes to prevent transfusion-associated graft-versus-host disease

L Corash1,2 and L Lin1

  1. 1Cerus Corporation, Concord, USA
  2. 2The University of California, San Francisco, USA

Correspondence: Dr L Corash, C/O Cerus Corporation, 2411 Stanwell Drive, Concord, CA 94520, USA. E-mail:



Transfusion-associated graft-versus-host disease (TA-GVHD) is a serious complication of blood component transfusion therapy. Currently, cellular blood components for patients recognized at risk for TA-GVHD are irradiated prior to transfusion in order to prevent this complication. Considerable progress has been made in elucidating the pathophysiology of this highly morbid complication, but questions as to which patients are at risk and what is the most robust technology to prevent TA-GVHD remain. As new technologies for inactivating or modulating leukocyte function are introduced, the question of how to evaluate these technologies becomes relevant. Over the past two decades, a number of research groups have explored technology to inactivate infectious pathogens and leukocytes contaminating cellular blood components. Few clinicians have an in-depth understanding of the methods or the criteria for selection of how to approach new technologies for leukocyte inactivation with potential to replace current methods. This mini review focuses on the salient aspects of current and evolving technology for prevention of TA-GVHD.


leukocytes, transfusion-associated, graft-versus-host disease


Current status of technology for prevention of transfusion-associated graft-versus-host disease

Transfusion-associated graft-versus-host disease (TA-GVHD) is a complication of blood component transfusion therapy with high morbidity and mortality.1,2 Initially described as erythroderma accompanied by rapidly fatal pancytopenia in immunodeficient patients, the syndrome was subsequently characterized as a form of GVHD following blood transfusion.3,4 Over the past three decades, the pathophysiology of TA-GVHD has been studied extensively, and the primary mechanism of action attributed to the proliferation of donor T cells in susceptible recipients following transfusion.5 By empirical experience, irradiation of blood components with either gamma or X-ray sources has been established as an effective means to prevent TA-GVHD.6 Despite the advent of widespread leuko-depletion by either automated collection technologies or filtration, irradiation remains the standard of care for prevention of TA-GVHD.7,8,9 Currently, cellular blood components for patients thought to be at risk for TA-GVHD are irradiated prior to transfusion in order to prevent this complication.10 Rare cases due to transfusion of viable leukocytes in fresh frozen plasma have been described as well.11

TA-GVHD has been reported following transfusion of components irradiated with conditions thought adequate for inhibition of T-cell proliferation assessed by using mixed lymphocyte reactions.12 These observations suggest that the safety margins for irradiation are narrow.13,14,15 Thus, while considerable progress has been made in understanding this highly morbid complication of transfusion therapy, questions as to which patients are at risk and what is the most robust technology to prevent TA-GVHD remain. In addition, as new technologies for inactivating or modulating leukocyte function are introduced, the question of how to evaluate these technologies becomes relevant.

Over the past two decades, a number of research groups have explored ways to inactivate infectious pathogens and leukocytes contaminating cellular blood components (Table 1). Recently, one of these methods received European regulatory approval and is entering clinical practice.16 The evaluation of new technologies that may replace gamma irradiation for prevention of TA-GVHD is challenging due to limitations of clinical trials to demonstrate prevention of TA-GVHD and the necessity of reliance on in vitro assays to document T-cell inactivation. Few clinicians may have an in-depth understanding of the methods or the criteria for selection of radiation doses to prevent TA-GVHD, or how to approach new technologies for leukocyte inactivation with potential to replace current methods.17 Thus, it is relevant to review the experimental evidence for methods of T-cell inactivation, in order to assess the efficacy of these technologies for prevention of TA-GVHD in comparison to that for gamma and X-ray irradiation.


Risk factors for TA-GVHD and current technology

The spectrum of patients at risk for TA-GVHD continues to expand with the advent of intensive immunosuppressive therapies, and with the recognition that even immune competent patients may be at risk for TA-GVHD (Table 2). The potential implication for TA-GVHD in patients with competent immune systems needs to be considered from two perspectives. Firstly, it is now recognized that in populations with limited HLA haplotype polymorphism (Table 3), patients not suspected to be at risk for TA-GVHD may be unrecognized to be at risk, and will not receive irradiated blood components as standard care. This situation was identified with the increased use of directed blood donations from related donors.18 It has also been recognized with the use of HLA-matched platelet components in alloimmunized patients.19 Even in the absence of TA-GVHD, another potential complication resulting from transfusion of viable leukocytes may arise from the establishment of long-term microchimerism in recipients.20 However, the implications of this situation are as yet unclear. With the increased awareness that blood transfusion therapy can induce serious adverse immune responses, greater attention has been devoted to methods for inactivation of T cells in blood components and to assay methodology to determine that appropriate inactivation was achieved.21

Until recently, the dose of irradiation required to prevent TA-GVHD was largely based on empirical grounds.22 The understanding of the relationship between the dose of gamma irradiation and T-cell viability was advanced by the use of a sensitive clonal T-cell proliferation assay with limiting dilution analysis (LDA) in order to define the appropriate dose of gamma irradiation.23 This assay was shown to be capable of detecting approximately a 105.5 reduction in viable T cells (Figure 1). The assay provided a rational means to set the dose of gamma irradiation for effective T-cell inactivation, and it documented that the dose response curve for T-cell inactivation was steep, such that with only slight reductions in the irradiation dose, T-cell viability was retained and thus the potential for TA-GVHD. Previous studies suggested that at higher irradiation doses platelet function may be compromised; and thus the tolerable dose of gamma irradiation may be limited.24

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Effect of gamma radiation dose on T-cell inactivation. The effect of increasing doses of gamma irradiation on residual T-cell proliferation was determined using a clonal T-cell proliferation assay. Increasing doses of gamma irradiation resulted in increased T-cell inactivation. Adapted from Pelszynski et al.23

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Novel methods to modulate T-cell function: technology beyond gamma irradiation

In the past decade, several nucleic acid targeted processes for inactivation of residual-contaminating viruses, bacteria, and protozoa in blood components have been investigated (Table 1). Nucleic acid targeted processes are well suited for leukocyte inactivation; however, only a few of these technologies have been evaluated for potential to inactivate leukocytes.

Experience with 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light had established the use of photochemical modification of leukocytes for treatment of cutaneous T-cell lymphoma25 and for treatment of stem cell transplant-related chronic GVHD.26 Both of these treatments were postulated to act via specific interactions with T cells. Starting in 1989, a series of research publications examined the utility of existing psoralens (8-MOP and AMT) and novel psoralens (amotosalen HCl) for the inactivation of infectious pathogens and leukocytes in platelet and plasma blood components.27,28,29,30,31,32,33,34,35,36 Recently, a photochemical process using amotosalen HCl has received European approval for inactivation of infectious pathogens and leukocytes in platelet components.37

This technology utilizes the novel psoralen compound amotosalen HCl, formerly known as S-59, and long wavelength ultraviolet light (UVA) to induce the formation of irreversible, covalent psoralen–nucleic acid adducts (Figure 2).38 Amotosalen differs from 8-MOP by introduction of a net positive charge resulting in greatly improved nucleic acid binding.38 Nucleated cells contaminating platelet components are effectively inactivated by photochemical treatment. However, platelets are anucleate, terminally differentiated cell fragments that do not appear to require residual nucleic acid for hemostatic function. The photochemical process results in sufficient preservation of in vitro platelet function properties.31,39 The inactivation of leukocytes and specifically T-cells using photochemical treatment has been extensively evaluated using a series of in vitro and in vivo assays. The following sections present a review of the data demonstrating T-cell inactivation for several of these technologies in the advanced stages of development.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Amotosalen HCl (S-59) Mechanism of action for leukocyte inactivation. Amotosalen HCl (S-59) is a positively charged amino-psoralen that intercalates into helical regions of DNA and RNA. In the absence of photoactivation, S-59 remains in a dark equilibrium with the nucleic acid. With UVA illumination, covalent monoadducts are formed between S-59 and pyrimidine bases. Addition of a second photon results in the formation of covalent diadducts or crosslinks. Viruses, bacteria, protozoa, and leukocytes containing sufficient numbers of monoadducts or crosslinks are unable to replicate or undergo repair.38

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T-cell inactivation as measured by a T-cell clonal expansion assay

T-cell inactivation can be measured using a T-cell clonal expansion assay with LDA. This assay has been used previously to measure the level of T-cell inactivation in gamma-irradiated blood products and was used by FDA to set the current guideline for gamma irradiation of blood products.23,40 The clinical dose of gamma radiation (2500 cGy) used for prevention of TA-GVHD results in a 105- to 106 -fold reduction in viable T cells. Using this assay with LDA, inactivation of >105.4 T cells/ml was demonstrated by exposure of platelet concentrates to 150 muM amotosalen and 3 J/cm2 UVA treatment. No residual colony-forming T-cells were detectable with this assay following photochemical treatment.

Additional studies using the LDA and lower doses of amotosalen and UVA were designed to determine the safety margin for photochemical treatment for T-cell inactivation in dose–response experiments (Figure 3). The results showed that T cells are extremely sensitive to photochemical treatment. At an amotosalen dose of 1500- to 3000-fold lower and with an UVA dose of approximately two-fold lower than the virucidal dose (150 muM amotosalen and 3 J/cm2 UVA treatment), T cells were inactivated to the limit of detection as detected with the clonal expansion assay. In contrast, gamma irradiation has a limited margin of safety. T-cell inactivation drops off rapidly with a modest decrease in the dose of gamma radiation (Figure 1). Supporting this observation, TA-GVHD has been reported in transfusion recipients who received blood components irradiated with 1500 cGy.15 Similar studies have been conducted with the nucleic acid targeted compound S-303 developed to inactivate infectious pathogens and leukocytes in red cell concentrates.57 This technology utilizes a class of compounds known as frangible anchor linker effectors (FRALES) that intercalate into nucleic acid and form covalent crosslinks without activation by UVA light. Incubation of red cell concentrates with S-303 (200 muM) for 8 h resulted in high levels of T-cell inactivation (>105).

Figure 3.
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Effect of amotosalen (S-59) concentration on T-cell inactivation. Dose–response of T-cell inactivation in platelet concentrates treated with varying doses of amotosalen HCl and a 1.4 J/cm2 UVA process. The photochemical treatment dose of amotosalen (150 muM) for viral and bacterial inactivation is indicated. The amotosalen dose required to inactivate T cells to the limit of detection (indicated by short arrows) is >1500-fold lower than the dose required for pathogen inactivation.

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Leukocyte inactivation as measured by expression of activation antigens and mixed lymphocyte culture assay

CD69 expression is an early marker of T-cell activation and is inhibited by the virucidal compound PEN 110 as well as by amotosalen photochemical treatment.41,42 Using a mixed lymphocyte culture (MLC) assay, PEN 110-treated leukocytes were unable to proliferate; however, this assay system has a limited dynamic range (101–102) compared to the larger dynamic range (105–106) of the clonal T-cell expansion assay with LDA.23

Leukocyte inactivation as measured by DNA modification

Measurement of DNA modification by methods designed to inactivate T cells provides direct physical evidence of covalent binding of compounds or physical damage to leukocyte nucleic acid. Amotosalen–DNA adduct formation with leukocyte genomic DNA was quantified with radioactive amotosalen using the viral and bacterial inactivation dose of 150 muM and a 3 J/cm2 UVA treatment. These conditions resulted in an average of one psoralen adduct per 83 base pairs (bp) of genomic DNA.33 In contrast, the clinical dose of gamma irradiation (2500 cGy) induces one strand break per 37 000 bp.43

Leukocyte inactivation as measured by inhibition of nucleic acid amplification

Preparation of platelet concentrates with pathogen inactivation conditions using 150 muM amotosalen and 3 J/cm2 UVA treatment inhibits amplification of selected nucleic acid sequences as measured by the polymerase chain reaction (PCR). This assay provides direct evidence of inhibition of nucleic acid replication. Amplification of a 242 bp sequence in the HLA-DQalpha locus or a 439 bp sequence in the beta-globin gene was reduced by >103-fold. In a parallel analysis of gamma irradiated (2500 cGy) platelets, leukocyte DNA was infrequently modified and the modification had little or no effect on PCR amplification of the same nucleic acid sequences (Figure 4). Similar data have been generated for PEN 110. Treatment with PEN 110 inhibited amplification of an 1850 bp product as well as a 245 bp product after 22 h of treatment.42 This is indicative of a high level of nucleic acid modification. In contrast, gamma irradiation (2500 cGy) did not inhibit nucleic acid amplification of these nucleic acid sequences.

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Inhibition of amplification of leukocyte genomic sequences after photochemical treatment using amotosalen (S-59) and UVA. DNA samples (1 mug) obtained from photochemically treated or gamma-irradiated platelet concentrates were amplified by PCR for a 242 bp sequence in the HLA-DQalpha locus and for a 439 bp sequence in the beta-globin gene locus. PCR amplification was carried out to 35 cycles. Control (untreated) DNA was serially diluted (1 : 10) and amplified (lanes 8–12). A positive (P) and negative control (N) were included. DNA from leukocytes treated with increasing doses of amotosalen (S-59=10, 100, and 150 muM) AMT (150 muM), 8-MOP (75 and 150 muM), or gamma irradiation (2500 cGy) was amplified without dilution (lanes 1–7). This assay provided a means to correlate functional T-cell inactivation measured in a cell proliferation assay, with direct modification of nucleic acid measured by radioactive adduct formation and with inhibition of specific nucleic acid sequences. After treatment with 150 muM amotosalen and 3 J/cm2 UVA, amplification of the HLA locus and the globin gene locus was inhibited (lane 3). Other psoralens (AMT and 8-MOP) demonstrated lower levels of inhibition, which correlated with reduced adduct density (Mod/1000 bp). In contrast, after treatment of leukocytes with 2500 cGy of gamma irradiation, amplification of these gene sequences was not inhibited (lane 7). This difference reflects the higher level of nucleic acid modification obtained with the photochemical treatment.

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Leukocyte inactivation as measured by inhibition of cytokine synthesis

Cytokine synthesis by contaminating leukocytes was measured after photochemical processing (150 muM amotosalen and 3 J/cm2) or gamma irradiation (2500 cGy) of platelet concentrates. Photochemical treatment completely inhibited cytokine synthesis during platelet storage.34 Gamma irradiation only reduced the levels of cytokines by approximately 40% during platelet storage. This observation is consistent with the level of nucleic acid modification achieved by photochemical treatment in contrast to that resulting from gamma irradiation since cytokines generally have DNA sequences of approximately 10 000 bp. PEN 110 treatment of nonleukoreduced red cell units stored at room temperature demonstrated inhibition of IL-8 production.42

T-cell inactivation as measured by murine transfusion models for TA-GVHD

In vivo studies were performed to demonstrate that photochemical treatment prevents TA-GVHD in well-characterized murine transfusion model. This animal model was selected because it accurately represents a paradigm in transfusion medicine, namely, that transfusion of blood products from first-degree relatives causes TA-GVHD in immunocompetent recipients.44,45

In this model, 108 splenocytes from an MHC homozygous parent were transfused into an immunocompetent MHC heterozygous F1 hybrid. The recipient lymphocytes recognized the donor cells as self and thus did not respond to and reject the donor cells. In contrast, the donor cells recognized the recipient cells as foreign and initiated a potent GVHD response against the recipient. With this model, acute TA-GVHD was induced in the F1 recipients. However, F1 recipients who received donor spleen cells treated with amotosalen HCl and UVA remained healthy and free of biological and clinical evidence of TA-GVHD. These in vivo results showed that pretransfusion photochemical treatment of splenocytes prevented TA-GVHD in the murine model.35

Similar studies have been conducted using immunocompromised mice undergoing bone marrow transplant.46 These animals are more sensitive to GVHD and are analogous to immunosuppressed patients undergoing ablative therapy with T-cell suppressive treatments. Other studies were conducted with both major and minor histocompatibility mis-matches with T-cell-depleted stem grafts.47 In these studies, transfusions of untreated donor T cells resulted in rapidly fatal TA-GVHD. In contrast, animals transfused with donor T cells treated with amotosalen and UVA survived without developing TA-GVHD and were engrafted with donor hematopoietic cells.47

The homozygous parent to F1 hybrid transfusion model also has been used by Fast et al 48 to evaluate the ability of the Inactine compound PEN 110 to prevent TA-GVHD. Treated cells did not cause TA-GVHD. Of interest PEN 110-treated splenocytes were unable to serve as allogeneic stimulator cells in a mixed lymphocyte culture (MLC) assay with either naïve or immune responder cells. In addition, PEN 110-treated splenocytes did not induce increased immunoglobulin production in a murine model for chronic GVHD.

Clinical experience with photochemical treatment for prevention of TA-GVHD

Platelet components prepared from whole blood using the buffy coat process and this photochemical treatment system were evaluated in a randomized clinical trial and demonstrated post transfusion count increments and hemostatic function comparable to conventional platelet components.37,49 In this clinical trial and two others, photochemical treatment was used for prevention of TA-GVHD without gamma irradiation for patients in the treatment groups assigned to photochemically treated platelets. The incidence of TA-GVHD after transfusion of photochemically treated platelets prepared without gamma irradiation was compared with that of conventional platelets treated with gamma irradiation for 166 patients.50 Photochemically treated platelets or conventional platelets (buffy coat or apheresis) were given for up to 56 days to thrombocytopenic patients with malignancies or therapies associated with risk of TA-GVHD. A total of 71% of patients given conventional platelets were considered at risk for TA-GVHD and received gamma-irradiated platelets. The Test patient group exhibited similar disease and treatment characteristics. In all, 93% of patients in the Test group received only platelets prepared with photochemical treatment. Patients in both the treatment groups received multiple platelet transfusions. No cases of TA-GVHD were identified in either group. These results support prior in vitro data and in vivo data, indicating that photochemically treated platelets are effective in preventing TA-GVHD in patients at risk for this complication.

In conclusion, photochemical treatment with the psoralen compound amotosalen HCl and UVA light and the Inactine PEN 110 effectively inactivates T cells as measured by sensitive in vitro assays and in animal models analogous to the types of patient populations at risk for TA-GVHD. Recently, clinical experience was obtained from European studies in which photochemical treatment with amotosalen and UVA light was used in place of gamma irradiation for prevention of TA-GVHD. The introduction of this technology offers the potential to further improve the safety of platelet components as well as to inactivate T cells in all platelet components rather than selectively irradiate components prescribed for patients suspected at risk for TA-GVHD. The development of methods to treat red cells with nucleic acid targeted compounds such as S-303 and PEN 110 should result in the extension of this approach to red cell components as well. This may further reduce the incidence of TA-GVHD as use of highly immunosuppressive therapies expands.



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Nature Medicine News and Views (01 Jan 1999)