Humoral rejection.


The cardiovascular sessions at Banff 2001 made an impact in several centers, which have recognized that humoral rejection is indeed a clinical entity.  Evaluation for humoral rejection is now commonplace at the following centers, UCLA, Cleveland Clinic (the two largest transplant programs in the USA), Texas Heart Institute, La Coruna in Spain    have been performing complement stains to assess humoral rejection in heart biopsies.  Johns Hopkins is now using routine immunofluorescence in all transplant biopsies.  The Utah group also share their vast experience with the evaluation of humoral markers.


However, the challenge ahead is to standardize the algorithms for the evaluation of humoral rejection in the heart.  Current practice ranges from C4d staining alone to assessment of C3d and C4d and other molecules including immunoglobulins and HLA-DR and fibrin in tissue.   No consensus was achieved in deciding the basic algorithm.  This will probably not happen until the first sets of series determining the incidence and methodology used for humoral rejection diagnosis are published.  It will then provide an accurate estimate of the true incidence of humoral rejection in cardiac allografts.  It was evident that clinical presentation with evidence of graft dysfunction is a rather useful piece of information that at this juncture is still important to collect in order to confirm that the pathologic criteria of humoral rejection achieve indeed sensitivity and specificity.


A new working formulation should suggest collection of serum samples even though the may not be used immediately for HLA determination.  Also there may be suggestion of which standard techniques for HLA antibody determination could/should be used in order to allow for comparability of data


It was widely agreed that in cardiac transplant patients we must consider endothelial cell, arterial wall or possibly myocardial antigens as the targets of humoral rejection in the absence of donor specific HLA antibodies.


It was agreed that the role of fibrinolytic / procoagulant molecules in the tissue deserves further investigation for is diagnostic and prognostic potential.  was discussed and thought to be worth exploring as an additional useful test to assess humoral injury to the graft.


The working formulation may include information about conditions that heighten the odds of developing humoral rejection (pregnancy, induction therapy, left ventricular assist devices).


One unexpected topic of discussion included issues that achieved consensus in 2001 and were raised by the Papworth and Middlesex groups expressing the need for further discussion of  histopathological criteria for the diagnosis of cellular rejection.

The issues that seem resolved by clarifying the light microscopic features of cellular rejection seem to be in controversial status once again.  The Papworth and Middlesex groups explained that elimination of Grade 2 cellular rejection may be beneficial for  quality control and compliance and standardization issues in the  United Kingdom.   Disagreement over the elimination of Grade 2 was voiced by the Hopkins and Cleveland George Pompidou group.  Particularly since the consensus in Banff 2001 was that elimination of Grade 2 rejection would lead to  controversy,  would eliminate a rejection grade that is used still in some center to make therapeutic decisions and lastly it would adversely affect the use of historical / archival material in tissue or data banks.


The ISHLT has made a decision to reevaluate likely to convene a panel to reevaluate and modify/update the working formulation and their intention is to do this along with the Banff initiative for cardiac allograft rejection.


In summary, while much work lies ahead, it is clear that big, medium and smalls centers from many countries recognize that this collaborative work is needed to improve diagnosis and consequently therapy and survival of cardiac allograft patients.