Transfusion related immunomodulation.pptx

Transfusion related immunomodulation

1. Transfusion Related Immune Modulation (TRIM )

2. Overview History Definition Postulated mechanism of action (Pathophysiology) Effects -Beneficial -Delirious Conclusion

3. HISTORY 1990 1981 1964 1980 1972 Halasz et al reported that dog given donor blood with a renal graft had prolonged survival Brunson Transfusion-associated immunosuppression Gantt Possibility of association between ABT and increased cancer recurrence Leukoreduction Opelz et al, multicentric prospective RCT of candidates of cadaveric RT received either AbT or no transfusion

4. DEFINITION-TRIM The constellation of all allogenic blood transfusion (ABT) related laboratory and clinical findings is known as TRIM It encompasses effects attributable to ABT by means of - Immunomodulatory - Pro inflammatory mechanisms TRIM can be seen as those potentially proinflammatory or immunosuppressive effects that can occur because of a transfusion due to mediators that are preformed and present in the unit or that are produced by recipient as a response to the transfusion

5. ABT ABT may either cause alloimmunization or induce tolerance. (presence or absence of autologous HLA-DR Ag on donors’s WBC plays a decisive role) Donor sharing atleast 1 HLA DR with recipient will induce tolerance whereas fully mismatched transfusion leads to alloimmunization.

6. In addition to the degree of HLA-DR compatibility between donor & recipient, immunogenicity of cellular and soluble HLA antigen found in transfused blood component depends on the viability of donor APC’s and the presence of the required co-stimulatory signals for the presentation of donor Ag to the recipient T cells Non viable APCs and/or absence of the requisite co-stimulatory signals result in T-cell unresponsiveness

7. ABT ABT has been shown to cause 1. Decreased helper T cell count 2. Decreased helper/suppressor T lymphocyte ratio 3. Decreased natural killer (NK) cell function 4. Reduction in delayed-type hypersensitivity 5. Defective antigen presentation 6. Decreased cytokines(IL 2,IFN) 7. Decreased monocyte/macrophage phagocytic function

8. Clinical relevance Benefits Risk Improved renal allograft survival Possible increased cancer recurrence Treatment of recurrent spontaneous abortion (where they share HLA ag with father) Possible increase perioperative infection Reduction of risk of Crohns disease Increased short term mortality in cardiac surgery Increase in the risk of reactivation of CMV and HIV

9. Why benefit from ABT If blood being transfused is already leukoreduced benefit obtained from ABT is minimal in renal transplant During refrigeration APC lose their ability to deliver co-stimulation Following ABT, the recipient’s T cell are stimulated by allogenic donor APC in the absence of co-stimulation

10. Mechanism of action Published literature has suggested that TRIM may be mediated by: -soluble HLA class1 peptides that circulate in allogenic plasma -soluble BRM released in time dependent manner from WBC granules/RBC membrane/Platelet granules during storage - Allogenic mononuclear cells

11. Mechanism of TRIM TRIM EFFECT OF ABT Allogenic WBC Soluble Biologic response modifiers Soluble HLA peptides ROS Proteolytic enzyme Pro inflammatory response Elastase Myeloperoxidase TGF beta Down regulation of recipients immune system

12. “ S econd immunological hit”-This implies that there must be a primary insult to the immune system that predisposes the transfusion recipient to TRIM

13. Biological response modifiers These mediators are contained in intracellular WBC granules, and are released in a time-dependent manner as WBC deteriorates. BRM -Histamine -Myeloperoxidase -Eosinophilic cationic proteins - Plasminogen activator inhibitor They have been shown to decrease neutrophil function--- devepolment of immunesuppression

14. MICROCHIMERISM When donor and recipient HLA compatibility is such that there is a persistence of small number of donor lymphocytes and APCs in circulation or organs of the ABT recipient Microchimerism results in release of - IL4, IL10 and TGF-beta from TH-2 Lymphocyte, these cytokines have been shown to inhibit the production of Th-1 cells and to deactivate cytotoxic T cells – suppressing allograft rejection It has been demonstrated in trauma patients only till now

15. Soluble HLA molecules Non polymorphic peptides derived from HLA class 1 molecules might induce antigen-nonspecific immunosuppression, whereas polymorphic HLA class 1 peptides have antigen-specific immunomodulatory effects It also seems possible that allogenic plasma containing soluble HLA antigen may enter the recipient’s thymic circulation, producing clonal deletion of the recipient’s T cells that are directed against the allogenic donor antiigens .

16. Soluble HLA molecules Ghio et al. and Puppo et al found soluble Fas -ligand ( sFasL ) and soluble HLA class 1 molecules in the supernatant plasma of RBC and RDP Infusion of sFAsL in transfused blood components may bind the Fas molecule expressed on the NK and cytotoxic T cells of recipient This impairs there function----impedes the apoptosis of viral infected cells

17. Effect on WBC on storage WBC apoptosis begins immediately after blood withdrawal with granulocytes, then monocytes while lymphocytes remain viable for 25days engages Releases TGF Apoptotic cells Annexin V / PS receptor on macrophage Suppressess macrophages/NK cells Impair APC capacity

18. Effect on WBC on storage Viable WBCs can act as a responder or as stimulator cells inducing cellular immunity or antibody production in the recipient 3-5d of storage Protein synthesis Responder capacity Capacity to stimulate R recipient T helper cell T cell Donor APC Functional phosphorylation defect Reduction in co stimulatory molecule

19. Potentially vulnerable populations Postoperative Trauma Sepsis Cardiopulmonary bypass Transplantation

20. Enhanced survival of renal allograft A multicentric observational study(58,036 renal allografts from cadaveric donors) indicated that patient who had received ABT were still more likely to have a successful renal allograft The beneficial effect of pretransplant ABT was though less important with advent of cyclosporine The graft outcome risk-benefit ratio has now become too high to justify consideration of pretransplant ABT when these can be avoided

21. Agency for Healthcare Research and Quality (AHRQ) reviewed all available clinical evidence and suggested, -pretransplant ABT has a neutral to beneficial effect on graft rejection, graft survival and patient survival Most current evidence appears to indicate that improvements in graft survival are now attainable without pretransplant ABTs Graft outcome risk-benefit ratio justified avoidance of ABTs as far as possible with the improvement in peri-transplant immunosuppression therapy

22. Recurrent spontaneous abortions (RSA) Fetus represents a semi-allogenic graft to its mother and maintenance of a pregnancy depends on immunologic equilibrium between the implanted fetus and the maternal immune response to the fetus Sharing HLA Ag (consanguineous marriage) causes alteration of this balance ASRI found ABT effect(9-10%) effective

23. Postulated benefits Reduced risk of crohns disease Pooled data from existing studies suggest that the recurrence rate in transfused vs non transfused patient is similar (37.5% vs 40.5%) Heterogenous studies(different follow-up periods and surgical interventions) Large RCT needed to establish beneficial effect

24. DELETERIOUS EFFECT Cancer Recurrence Possible recurrence of cancer by ABT(or with TRIM ) has been examined in literature (100 observational clinical studies and 3 RCT) Still more evidence based study is needed to confirm the same

25. Postoperative infections Association with perioperative ABT and postoperative infection Meta analysis by Vamvakas et al found no significant association between the outcomes of patient that received ABT vs those that did not. WBC-containing ABT in particular have been implicated or associated with multi-organ failure in few studies.

26. Proposed mechanism of ABT AND MOF

27. Increased risk of short term mortality (3 months post transfusion) This RCT has been designed to investigate an association between non WBC reduced ABT and postoperative infection but instead observed an association between non WBC reduced ABT and mortality. Non WBC reduced ABT predispose to MOF and hence increased mortality Most evidence suggest that tissue injury is mediated by reactive oxygen species and proteolytic enzymes released from activated neutrophils

28. Leucoreduction Reduces CMV,EBV,HLA alloimmunization,Bacterial contamination Sparrow et al demonstrated that prestorage LD may help in abolishing TRIM Only post op cardiac patients have demonstrated a benefit in reduction in postop infection

29. Fresh vs Old RBC Older RBCs result in greater decreases in cytokine production including interleukin (IL)-10, IL-17a, interferon (IFN)-g, tumor necrosis factor (TNF)-a, and granulocyte macrophagecolony -stimulating factor compared to fresh RBCs. However, RBCs may not need to be stored for long time periods to exert an immune effect. RBCs stored for as little as 2 - 3 weeks can inhibit both CD4þ and CD8þ T cells stimulated with anti-CD3/CD28, inhibit B cells stimulated with lipopolysaccharide, and both of these effects could be reversed by transfusing fresh RBCs.

30. Association of WBC containing ABT with postop infection Rossi 5 th edition

31. Rossi 5 th edition

32. Association of WBC containing ABT with short term mortality Rossi 5 th edition

33. Association of WBC containing ABT with cancer recurrence Rossi 5 th edition

34. Methodological problems in the study of TRIM Numerous observational study, insufficient prospective double blinded RCTs Likelihood of confounding factors(patient characteristics- patient receiving transfusion are different from those not receiving transfusion) Widespread introduction of universal luecoreduction decreases the opportunity to perform RCTs

35. Conclusion TRIM is a real biological phenomenon, one established beneficial effects in human(augmentation of renal allograft survival) however various deleterious effects has not been confirmed yet RCT which is consistent with establishing adverse effects is in cardiac surgery patients( leucoreduced blood reduce the short term mortality from all causes) Clinical studies needed to elucidate the mechanism and clinical significance of pro inflammatory effect of non WBC reduced blood

36. Conclusion It is difficult to reach firm conclusions about the existence of adverse effects, or to make definitive recommendations The available RCT’s have not demonstrated a benefit from autologous transfusion in preventing adverse TRIM effects

37. Summary slide