blood transfusion and constituent transfusion

Blood transfusion and constituent transfusion

A. Brand and EL Lagaaij

Department of lmmunohaematology and Blood Bank, University Hospital, Leiden, The Netherlands

Current Opinion in immunology 1989, 1:118+1190

Introduction

Approximately one in five blood transfusions (BT) results in some adverse effects in the recipient (Walker. Am J Clin Path01 1987, 88:374378). Serious side effects occur in 0.51% of cases. These are: viral hepatitis (0.5%, emerging to chronic active hepatitis in 50% of these cases, of which 10% develop cirrhosis); non-car- diogenic pulmonary distress caused by leukocyte antibodies in donor plasma (0.02%), and acute or delayed type haemolytic transfusion reactions (0.045%). A rare severe complication, mainly occurring in middle-aged fe- males who have been pregnant and lack the platelet ZWa antigen, is post-transfusion thrombocytopenic pur- pura. Other BT complications, e.g. transmission of cy tomegalovirus ( f l%, increasing with multiple transfusion to lo%>, or Epstein-Barr virus (0.5%), only cause serious morbidity and mortality in immunocompromised patients. Cytomegalovirus seronegative recipients, in particular, suffer from the severe morbidity. Evidence is growing that kidney graft recipients can benefit from cy tomegalovirus vaccination (Plotkin, Luncet 1988, k1136). The formation of antibodies against the human leukocyte antigens (HI.& 10% after single BT, increasing to > 50% after multiple BT) is deleterious for recipients of platelet transfusions and patients awaiting transplantation. The presence of HLA antibodies reduces the chance of a cross-match-negative organ and results In a pro- longed interval before a suitable organ becomes avai- able. Patients with HIA antibodies develop febrile transfusion reactions after standard non-leukocyte-depleted blood components.

The formation of irregular ant.-elythrocyte antibodies occurs in l-2% of recipients after single BT, but may increase to > 30% in patients with chronic haemolytic anaemia. Red-cell matching for Rh and Kell antigens may reduce immunization in these patients, especially when red cell transfusions are started after 1 year of age (Michail-Merianou et al, VOX Sang 1987, 52:95-98). Depression of elythropoiesis and dose-dependent iron loading are inevitable sequelae of red cell transfusion.

Human immunodeficiency virus transmission, transfusion-mediated malaria and graft-versus-host disease are

extremely rare complications, but are often fatal because these complications are either not recognized or there is no available therapy. BT are also associated with immunosuppressive effects in the recipient, which may last a lifetime (Tamer et al, VOX Sang 1989,56:80-84). These immunomodulatory effects of BT do not necessarily im ply that there is an adverse effect; the immunosuppressive effect of BT can for instance, be deliberately used to enhance organ graft sunival.

The immunosuppressive blood transfusion effect General considerations Pretransplantation BT are associated with enhanced graft survival in kidney and cardiac allograft recipients. Bone marrow graft recipients show the opposite effect (Storb et al., Blood 1973, 54:477-&G). Thus, in contrast to untransfused patients, immunocompetent patients with aplastic anaemia or thalassaemia may reject HI.&identical mixed lymphocyte culture (MLC) negative grafts after multiple BT.

Gradually, during previous years, the donor-recipient matching for the major histocompatibility complex (MIX) antigens has improved as a result of the avai- ability of serological typing for HI_4 class II antigens (DR antigens). In addition, cyclosporin was introduced as a potent anti-rejection immunosuppressive drug. Both developments have contributed to improved kidney graft survival, and the necessity for the additional immunosuppressive effect of pretransplant BT has recently been questioned (Luncet 1988, i:565570). The final effect of BT on graft survival is certainly influenced by the degree of compatibility between kidney donor and recipient [ 11 or heart donor and recipient (Kerman et al., Transplan- tution 1988, 45:333-337). Because the BT effect is most pronounced in HLA-mismatched organ/recipient combinations, strategies could be developed to limit the number of pretransplantation BT and to restrict BT to sub- groups of patients. In patients with a high risk for immunization, e.g. after previous pregnancies or previous grafts, omitting pretransplant BT can be considered, if

1184

Abbreviations BT- blood transfusion: CML-cell-mediated lympholysis; DSTAonor-specific transfusion; HLA-human leukocyte artgem;

Ig-- Immunoglobulin: MHC major histocompatibility complex; N-mixed lymphocyte culture; UVm-Pultraviolet light.

@ Current Science ltd ISSN 0952-7915

Blood transfusion and constituent transfusion Brand and Lagaaij 1185

there is a high probability of finding a matched kidney donor. This probability may be estimated from race and HIA type of the recipient or the presence of a living-related donor [ 1,2].

of ‘high-dose’ tolerance. Enhanced graft survival can be obtained in rodents when purilied erythrocytes are given in larger amounts. Platelet transfusions, although provid- ing lO@fold more class I antigens compared with leukocytes, do not reliably enhance graft sutvival. This is presumably due to lack of standardization of platelet prepa- ration methods, resulting in variable contamination with

Which blood constituent and how many

transfusions?

class-II bearing white cells. Although one pretransplant BT is enough to obtain a signiiicant improvement of graft survival compared with

The beneficial effect of pretransplant BT on kidney graft non-transfused recipients (Fig. lb; Persijn et al, Tram survival has been known for 15 years (Opelz, Tru~lunt plant Proc 1977, 9:503505), retrospective and non-ran- Prcx 1973,5:253), but hardly any prospective clinical randomized studies demonstrate that there is a cumulative domized studies have been performed. One randomized effect on enhancing graft survival with increasing num- study (Persijn et al., Transplantation 1979, 28:39&401) bers of transfusions. The mechanisms of the BT effect, showed that when a limited number (l-3) of pretrans- exerted after one or a few BT, are presumably differ- plant transfusions were administered, leukocytes present ent from those by which multiple BT induce an effect. A in the red cell concentrates were essential. No beneficial substantial number of multi-transfused patients develop effect on graft survival was found in recipients transfused anti-HLA antibodies. The apparently cumulative BT effect with l-3 units of liltered, highly leukocyte-depleted, red is consequently influenced to an unknown extent by se- cells (Fig. la). Considering the high levels of MHC class I lection for a better matched kidney by a negative cross- antigens expressed by erythrocytes and residual platelets match. in 1 unit of filtered blood (Everett et al, Trurqduntution Besides this selection of non-responder patients, multi- 1987,44:123-128), the presence of class E-bearing white ple BT definitely result in lmmunosuppression. Patients cells seems essential to obtain an immunosuppressive BT receiving chronic BT therapy for haemolytic anaemia or effect in humans when one, or a small number of BT haemophilia all develop abnormally low T helper cell to are administered. This may be different from induction suppressor cell ratios, decreased proliferative T cell ftmc-

Survival Wo)

90

80

70

60

50

40

30

(a) (b)

6 12 24 36 48 60 6 12 24 36 48 60

Follow-up time (months)

Fig. 1. (a) Cadaveric kidney graft survival in a prospective blood transfusion study. 40 patients received one standard blood transfusion ). 12 patients received l-3 units of highly leukocy epleted blood f-j. fb) Cadaveric kidney graft survival in a retrospective study. atrents received one standard blood transfusion ( 74 patients had never been transfused and/or had never been pregnant cm).

ted from Persijn et a/. (Lancet 1984, ii:1043-1044).

1186 Transplantation

tions in vitro and decreased natural killer cytotoxicity (Kaplan et al., Blood 1984, 64308-310).

Finally, the optimal number of BT may be dependent on immunogenic factors in the recipient. For instance DIM- bearing individuals are recognized as high responders against incompatible organ grafts. They also show dispar ity from non-HLA-DFW6 graft recipients with regard to the optimal number of BT required to enhance graft survival (Fig. 2; Lagaaij et aC, Tramplantation 1987, 44:78%791).

Immunogenetics

Animal studies The immunogenetics of the BT effect must be deducted from experiments in animals. Most animal work ad-

dressed the question of homology between blood donor and organ donor. A few studies on homology in relation to h4HC differences and compatibilities between blood donor and recipient were confusing. Variations in results can be due to strain combinations and the different quan tities, sources, processing and timing of pretransplant transfusions. The consistent results that have arisen from animal studies are summarized below. Low dose tolerance

(1) Donor-specific transfusions (DsT) are more effec- tive than third-party BT.

(2) Third-party BT in most strains enhance organ graft survival when hlHC antigens are shared between blood donor and organ donor. Sharing of class II antigens gives the same results as sharing the whole MHC [3].

Graft 100 . I survival

after (a)

3 years 80-l 70

80

Number of blood transfusions

Fig. 2. (a) Influence of thenumberof pretransplantation blood transfusions on 3-year graft survival in DRw6+ recipients of a first cadaveric renal graft. The number on top of the bars repre- sent the number of transplantations. (b) DRw6- recipients show a cumulative blood transfusion effect on subsequent graft survival. Adapted from Lagaaij et al. (Transplantation 1987, 44, 78&791).


(3) In some strains, a third-party BT may show suppression through sharing of minor histocompatibility antigens (mH) or putative cross-reactive antigens shared between blood donors and organ donors even if the blood and organ donors do not share MHC antigens.

High dose tolerance

(4) Enhanced graft survival can also be obtained with third-party class I-bearing cells (erythrocytes), but only when given in larger amounts, from multiple donors including those which share MHC class I antigens with the organ donor [4].

A genetic system distinct from MHC, which has not yet been extensively studied in relation to BT immunomodulation, is the T cell receptor set of genes. These genes are analogous to the variable region (V) genes of immunoglobulin and make up the T cell repertoire (Hedrick et al, Nature 1984, 308:153158). The possi- bility that putative cross-reactive antigens, distinct from the MHC, are T cell receptor antigens has not been excluded.

Immunogenetics in humans In humans, a comparison between donor-specific BT and third-party BT can only be evaluated in recipients receiving kidney grafts (often haplo-identical) from living donors. Graft survival was improved in patients who received a DST compared with non-transfused patients. One study (Opelz, TrampluntProc 1985,17:1015-1022) showed similar excellent results when third-party BT were administered to recipients of (haplo-identical) kidney grafts from living-related donors. In cadaveric transplantation this comparison cannot be made, but our own preliminary observations indicate that when MHC is shared among third-party BT donor and organ donor, graft survival is improved after a single BT (Iagaaij et al, J Cell Biocbem 1984, 13a). In the population, the chance of one or two DR antigens being shared between blood donor and organ donor is f 50%. As BT in dialysis patients are given sequentially, the first BT may have a major impact on immune suppression, as has been shown in animal studies (Ludwin and Singal, Tranqduntation 1988, 45:n7-783).

Besides the effect of sharing DR antigens between blood donor and organ donor, there is also an effect of DR sharing between BT donor and recipient (Lagaaij et aL, personal communication). A beneficial effect on HLAAB compatible and incompatible kidney graft survival was only observed in recipients who received one BT from a donor sharing at least one DR antigen (Fig. 3a). One transfusion mismatched for both DR antigens resulted in immunization of the recipient, reflected in poor graft survival, especially in case of a repeated mismatch when blood donor and graft share HLAAB antigens (Fig. 3b).

Mechanisms of the effect of pretransplantation blood transfusions

The presumed mechanisms responsible for the immunosuppressive BT effect have been extensively discussed previously and are summarized below in Iive sections.

Selection of responder versus non-responder patient populations As mentioned previously, multiple BT can induce HLA alloimmunization. This may result in a selection of a we& matched organ by a negative cross-match. Although this phenomenon contributes to better graft survival in transfused recipients, this does not account for all the irr- munosuppressive BT effects. Immune tolerance can be obtained without the induction of HLA antibodies. Fac- tors which determine the production of HLA antibodies resulting in a positive cross-match are different from the factors determining rejection (Burlingham et al., Tram plantation 1988,45:342-345). Donor-specific BT administered with azathioprine generally result in a reduction of HLA antibody formation from 30 to 10% in prospective kidney graft recipients with maintenance of the tolerizing effect.

Clonal deletion of anti-donor-reactive T cells The clonal deletion hypothesis is also based on the al loimmunizing effect of BT. After the primary immunization of a BT, the graft acts as a secondary stimulus. The ensuing activated cell populations may be more sensi- tive in vivo for immunosuppressive drugs than resting cells, resulting in their eradication. To enhance this process further, high-dose methylprednison or antithymo- cyte globulin given initially after grafting should reduce DST rejection crisis in haplo-identical grafts from about 60 to 13%, as discussed by Burlingham (Tran.@hnta- tion 1988, 45:127-132). A related, but presumably distinct, phenomenon is specific cell-mediated lympholysis (CML) non-responsiveness towards the kidney donor which slowly develops in patients with long-term sta ble graft function (Goulmy et al, Transplant Proc 1981, 13:1607-1609).

Induction of suppressor T cells/mechanisms After BT. the MLC reaction and the subsequent CML can be normal, increased or decreased. Animal studies showed that different responses can be found depending on the lymphoid compartment used [ 5 I. Although the (blood) donor-reactive lymphocyte populations can be reduced, most studies have shown that these donor reactive lymphocytes are still present after BT. Prolifer- ative and cytotoxic organ-donor-directed T cells can be isolated from non-rejected kidneys [ 61. This implies that such T cells are blocked or inhibited in vivo, or that they are not able to initiate primaty graft rejection. This may be different for the second-set rejection reaction,


Graft survival

P/o)

22N

t

(a)

IN ON

50

Shared AB

antigens between

blood and kidney donor

25 25

0 0

IN

(b)

Shared AB

antigens between

blood and

kidney donor

2 4 6

Follow-up time (years)

Fig. 3.(a) Cadaveric kidney graft survival in 32 patients who received a DR (one or two antigens) -shared blood transfusion and subsequent grafts sharing 2 1 and 0 AB antigens (+) with the blood transfusion donor. Number of patients: 13 (m); 12 cm); 7 (I); P = 0.04. (b) Cadaveric kidney graft survival in 30 patients who received a two DR antigen-mismatched blood transfusion with subsequent grafts sharing 21 and 0 A8 antigens with the blood transfusion donor ( +). Number of patients: 8 (I); 17 CD); 5 (m)P = 0.02.

which can be mediated by cytotoxic T cells as well as an tibodies. In vitro, blocking of the proliferative response in a MLC has been found shortly after BT with lymphocytes derived from peripheral blood and various lyn- phoid organs. In vivo, passive transfer experiments in dicate that suppressor cells develop after BT. These cells may be derived from the T cell lineage (antigen-specific) or macrophage lineage (aspecific). The nature of the suppressor cells and how they interact with their targets has not yet been established. As the MLC is generally found to be more inhibited than the generation of cytotoxic cells as measured in a CML, the target for suppression may be a CD4+ recipient helper cell or an antigen-presenting donor cell. The ef- fector cell mediating suppression might be a suppressor cell or a cytotoxic T cell directed towards autologous or donor cells. Also, both mechanisms may be activated by BT. In a local graft-versus-host inhibition model, it was found that BT given subcutaneously or intravenously had two distinguishable effects: the development of recipient cy totoxic cells directed against donor lymphocytes with receptors for recipient MHC, or suppressor cells inhibit- ing the recipient anti-donor MLC. The generation of cytotoxic cells or MLC-suppressing cells was dependent on the route of administration of the BT. but both mech-

anisms resulted in inhibition of local graft-versus-host disease (Kosmatopoulos et al, Transplantation 1988, 46:570-574).

The generation of MLC blocking factors Data are accumulating that suggest that a sequential col- laboration develops between humoral and cellular factors in the induction of maintenance of allograft survival due to anti-donor suppression. In the same way as with the recipient-derived donor-specific MLC blocking cells mentioned above, soluble MLC blocking factors are also found. These factors were detected in the im munoglobulin (1g)G fraction of the recipient serum. A large variety of antibodies, however, are known to inhibit MLC reactions. Such antibodies can be directed against DR antigens of the allogeneic stimulatory antigen-presenting cell, against Fc receptors or cell adhesion and activation antigens (Ma&& et al, Tralzrglant Proc 1983, 15:101~1021). Such antibodies can also interfere with the receptor for alloantigens on autologous cells (Singal et al, Transphnt Proc 1985, 17:1104-1107). The presence of serum factors (partially) blocking the MLC is associated with improved renal graft survival (de Haan et al, Trarq!duntution 1988, 46:581-584; Burling- ham et al., Tran.pluntution 1988, 45342-345). Block- ing factors in serum have also been found after liver


transplantation (McDonald et al., Transplantation 1988, 46:474-475).

induction of anti-idiotypic antibodies After BT, antibodies reacting with allo-anti-HLA antibod ies against class I as well as class II antigens can be found (Barkley et al, Tranghntation 1988,44:3&34; de Haan et al, 1988). Anti-isotypic antibodies cannot be excluded as in most instances the experiments were carried out with platelet-absorbed serum or IgG fractions but rarely with FalYz. The presence of such cross-reactive anti-idiotypic and/or anti-isotypic antibodies correlates with enhanced graft survival in general but their presence is not predictive in individual patients. This can easily be ex- plained by the fact that the patient’s sera were tested against available arbitrarily chosenanti-HIA class I and II set-a, which suggests a high degree of sharing of (pub- lic?) idiotypes among individuals. This, however, does not have any bearing on the role of these antibodies in the individual’s private network. Anti-HIA antibodies can dis- appear; this may occur in up to 50% of the recipients of multiple BT that either do not respond or respond temporarily to BT with the formation of HLA antibod ies (Murphy et al, Br J Haemutoll987, 67:255-260). A correlation with kidney graft survival and the presence of anti-idiotypic suppression of autologous HLA antibodies was established (Reed et al, N En@ J Med 1987, 316:145&1455).

BT-induced tolerance: activation or

suppression

A large part of the body’s lymphocytes and antibodies is not directed against antigens in the environment but is in- stead involved in self-recognition. It is tempting to spec ulate that BT- and organ graft-induced tolerance would ideally result in a condition in which alloantigens are ret ognized as autoantigens [ 71. The network involved in this process of autorecognition and tolerance may also show a high degree of cross-reactivity among individuals.

The balanced network for auto- and alloimmunity may be pertubed by dendritic cells and, to a lesser extent, by class II-bearing monocytes (Iechler and Batchelor, J Ez@ Med 1982, 155:31-35; Oluwole et al., Tranqlanta tion 1988,46:352-358). This could explain why, in bone marrow transplantation, activation of the marrow recipient resulting in graft rejection overrules the immunosuppressive effect of the often numerous pretransplantation BT, as bone marrow is very rich in dendritic cells. Also viral infections, which by releasing interferon y and other lymphokines increase the expression of class II antigens on auto- and allogeneic cells, can be responsible for a breakthrough in the balanced network.

What is the future of the pretransplantation blood transfusion?

The immunomodulatory effects of BT in induction of enhanced organ graft survival are multifactorial. Presumably, different mechanisms operate for one or a few (donor- specific) BT, and for multiple BT. The immunosuppressive effect of one of a limited number of BT seems largely dependent on sharing of MHC antigens between organ donor, blood donor and recipient. Multiple BT may result in immune unresponsiveness by several interacting mechanisms in which the role of MHC antigens may not be very speciiic. However, considering the frequent dan gerous and troublesome adverse reactions to BT, it is extremely important to understand and manipulate the im munosuppressive effects of a single BT. An important ap- proach to further understanding of the mechanism is HI.A typing of the single BT donor and the use of randomized studies with single BT selected on the basis of sharing MHC class II antigens or a disparity with the recipient. With regard to alloimmunlzation, new approaches can be expected. In animal studies, BT have been manipulated with drugs such as Carbodiimlde (Pepino et al, Transpkantation 1988, 45:66%70) or by ultraviolet light (I-IV) B treatment [8]. Such treatments effectively reduce the immunogenic potential, and subsequent antibody formation, but still show maintenance of immuno- tolerance towards blood donor antigens and subsequent grafts. These developments are extremely promising. It may even be expected that an immunosuppressive effect will be obtained in bone marrow transplant recipients. Once it is established that such treatments do not interfere with haematopoietic stem cells, graft-versus-host disease may even be prevented by UV-B treatment of the bone marrow. Both approaches, immunomodulation by a single BT and reduction of alloimmunization, may help to determine which blood component from which donor induces the best conditions for graft tolerance for a particular patient (e.g. post-pregnancy, rare HLA-type, black) awaiting a particular organ or bone marrow transplanta tion (cadaveric, living-related, matched unrelated).

Conclusion

It seems to us that pretransplantation BT should not yet be abandoned, and it is still not too late to develop ran domized clinical trials to study the effects of BT. Finally, we will briefly discuss the use of BT to modu- late autoimmune disease and the effect of BT on cancer surveillance. Treatment of diabetes mellitus with third- party BT led to contradictoty results in animals (Hanafura et al, Diabetes 1988, 37:204-208) and man (Cavenough et al., Diabetes 1987, 36:1089-1093); this may well be related to differences in timing of BT before and after the onset of the disease. The observation in animals that allo-


regulation interferes with autoregulation is intriguing, as it was assumed that distinct cellular and humoral networks existed for self and non-self regulation. Manipulated (in vitro expanded?) autologous blood constituents may still serve this purpose better. The effect of BT on cancer im- munosurveillance was the subject of many retrospective studies with contradictory conclusions. Fortunately, sew eral prospective randomized studies comparing the effect of autologous and various other blood constituents on cancer recurrence are currently underway.

Annotated references and recommended reading

0 Of interest ??o Of outstanding interest

1. CECKA JM, CICCIARELU J, Mtctoz MR, TE~U~AKI PJ: Blood 0 transtiions and HLA matching - an either/or situation

in cadavetic renal transplantation. Trun@kzntution 1988, 45:8185.

6000 primary cadaver donor renal transplants treated with cyclosporin were analyxd for the BT effect in relation to the w-match of the graft. Transfusions accounted for a signikcantly improved graft survival rate, mainly ln poorly matched donor-recipient pairs.

2. COLoMBE BW, JUSTER RP, SALVAT~RA 0 JR, GAROVOY MR: Pre- ?? diction of donor-specific tran.&sion sensitization: I. A lin-

ear logistic model. Tra~hntution 1988, 45:101-105. 195 patients recehing DST were analysed for risk factors for developing HIA antibodies. 67 factors were identihed to help estimate the probability of sensitization which may lead to the de&ion either to omit pretransplant DST, or to combine BT with immune suppressive drugs.

3. PEUGH WN, Wool KJ, Mo~ats PJ: Genetic aspects of the 0 blood transfusion effect. Trulyplantation 1988, 46:438443. In murlne cardiac a&grafts, the sharing for MHC (class II) antigens, mi- nor antigens (mH) or no antigens of third-party BT was valuated after single BT. Whereas DST and third-party BT sharing MHC ( + mH) antigens with organ donor always resulted in enhanced graft survival, sharing of mH alone proved to be insufficient for graft enhancement, Un- expected graft-enhancing effects of third-party BT were found in combinations not sharing MHC or mH. Putative cross-reactive antigens may have a role.

i. BALRD MA, HESLOP RF: The importance of specificity in the . transfusion effect. Tran.pkzntution 1988, 45&f&668.

In a cardiac allograft murine model the immune suppressive effect of class II-free, class I-expressing etythrocytes was shown to be dosede- pendent, but independent of shortened red-cell survival, which may rep sult in aspecific inhibition of macrophage function. This type of BT-in duced suppression needs larger amounts of blood and multiple donors, among whom there must be a donor sharing class I with the organ donor.

5. QUIC~EV RI, WOOD KL, MORRIS PJ: Investigation of the mech- 0 anism of active enhancement of renal allograft survival by

blood transfusion. Immunology 1988, 63:373-382. In 4 rat strain combinations, the donor-specific proliferative and cytotoxic responses were studied after BT. Depending on the lymphoid compartment from which lymphocytes were derived, decrease (lymph node, thomcic duct) or increased (spleen) responder functions in MLC were observed. The cytotoxlc cells generated in the MLC were normally present and not impaired in case of a reduced MU: response. Cytotoxic cells were also normally present in animals with enhanced graft survival in uivo.

6. RUV. P, COFFMAN TM, HOWELL DN, STRAZNICKAS J, SCROGGS MW, ??e BALDWIN WM III, KLOTMAN PE, SANFIL~PPO F: Evidence that

pretransplant donor blood transfusion prevents rat renal allograft dysfunction but not the in situ celhdar alloimmune or morphologic manifestations of rejection. Tran.pkzntution 1988, 45:1-7.

In a rat renal allograft model, graft survival was lndesnitely enhanced by DST in contrast to autologous BT. Enhancement of graft survival after DST was associated with reduced thromboxane production. The presence of alloreactive cytotoxic and helper T cell populations in the kidney were equivalent in rejected post-autologous BT functioning post- DST kidneys.

7. CONTIN~O A, BANDEIRD A: Tolerize one, tolerize them ail: on me assertion versus ignorance of self as the basis for tolerance.

Immunology Toaizy 1989, in press. Self-tolerance is postulated to be mediated by a ‘positive dehnition of self by naturally activated autoreactive lymphocytes induced by (self) antigens at critical stages in ontogeny. Such a hypothesis has conse- quences both for the strategies for induction and the monitoring of BT- and organ-induced tolerance.

8. OLUWOLE SF, CHAESOT J, PEPIN P, REEMTSMA K, HARDY

b MA: Mechanisms of immunologic unresponsiveness induced by ultraviolet-irradiated donor-specific blood transfusions and peritransplant cyclosporine. TnmpZantution 1988, 46352-358.

In a heart transplant model in rats, UV-B-treated DST and short-term q- clospodn treatment resulted in indefinite graft survival. Both donor-spe ciiic cellular and humoral suppression was observed. In vitro, the irradi ated suppressor cell and the post-transfusion semm showed donor-specific MIC inhibition. Adoptive transfer experiments showed a modest but significant enhanced heart survival rate with both post- W-B BT cells and serum.

blood transfusion and constituent transfusion

Documents