Recent discoveries have suggested that the exchange of multiple leukocyte lineages between grafts and host and subsequent long-term chimerism in both is the seminal mechanism of the acceptance of organs transplanted from the same (allografts) or different species (xenografts). This insight suggests new strategies which may allow xenotransplantation, the principal obstacle to which has been humoral rejection. We have defined humoral rejection as a family of complement activation syndromes afflicting allografts and xenografts in which there is a strong (but not invariable) association with preformed antigraft antibodies, invariable evidence of complement activation, histopathologic stigmas of vascular endothelial damage, and a concomitant local or systemic coagulopathy. The generic descriptive term hyperacute rejection is a misnomer because a slow-motion version of the same “humoral” process can occur with some allografts and is the rule with the so-called concordant species xenotransplantations. The pathway of experience and discovery leading to this conclusion shows clearly that the distinction frequently made between allograft versus xenograft humoral rejection does not actually exist in principle, but only in details and intensity.

Breaking down this barrier to xenotransplantation, whether or not it is associated with antibodies, is unrealistic. However, the possibility of avoiding the barrier has been exposed by showing that animal organs can be humanized, with a mixed donor and recipient cell population similar to the chimerism seen in long surviving allografts or even with complete leukocyte replacement. Pilot experiments in rodents suggest that organs from fully xenogeneic chimeras can be made into xenogeneic targets that are no more provocative of complement activation than allografts when they are transplanted into the donor bone marrow species. Although the validity of this concept of organ xenograft preparation is only at the pilot stage of verification, there is reason to suspect that the complement trigger of humoral rejection can be thereby disarmed. If this can be accomplished, independent evidence suggests that cellular rejection can be controlled with conventional T-cell directed immunosuppression, perhaps even with surprising ease. The potential subtle liability of synthetic products of xenogeneic parenchymal cells is not yet known.

/pdf/the-biological-basis-of-and-strategies-for-clinical-r3jutguil7.pdf

The biological basis of and strategies for clinical xenotransplantation.

Thoracic duct drainage (TDD) was established for 21-115 days in 40 kidney recipients with an average removal per patient day of 4.7 1 lymph and 1.88 billion cells. Cellular and humoral immunity were depressed. TDD and immunosuppressive drugs were started at transplantation in 35 recipients of cross-match negative grafts. Although the results were better than in precedent non-TDD controls, eight patients rejected their grafts before a full TDD effect, and three of the eight developed predominantly anti-B lymphocyte cytotoxic antibodies which were probably responsible for positive cross-matches with their next donors. With continuing TDD, all eight patients had good initial function after early retransplantation. In five more “nontransplantable” patients with performed cytotoxic antibodies, TDD was started 30-56 days before transplantation. In these five pretreated patients, antibodies persisted with positive antidonor cross-matches. Hyperacute rejection occurred repeatedly in two patients with high anti-T (and anti-B) titers, but was surmounted in three patients with lower titers. From the clinical and immunologic data, we have concluded that TDD should be used for pretreatment of all cases with or without prior antibodies, and have suggested an adjustable management plan that takes into account new developments in antibody monitoring.

/pdf/thoracic-duct-fistula-and-renal-transplantation-5gdx1gz0yj.pdf

Thoracic duct fistula and renal transplantation

Twenty-seven consecutive recipients of cadaveric kidneys, including five with pre-existing warm cytotoxic antibodies, were treated with thoracic duct drainage before and after transplantation. Fourteen patients who had lymph drainage for 26 to 58 days before transplantation had minor cytotoxic antibody responses after grafting, even if the antibodies had been present before therapy. Only one of the 14 recipients had any rejection during the follow-up periods of one to six months. There were two deaths. The 13 patients pretreated for 17 to 23 days exhibited stronger cytotoxic antibody responsiveness, and five of these recipients had significant rejections of which four were reversible. One of the latter 13 patients died. These clinical and immunologic studies have established the value and have defined the appropriate timing of preoperative thoracic duct drainage in kidney transplantation. They have also directed attention to the rationale and the probable value of using other immunosuppressive methods for preparatory host conditioning instead of beginning such therapy at the time of transplantation.

/pdf/thoracic-duct-drainage-before-and-after-cadaveric-kidney-2vcb9oiara.pdf

Thoracic duct drainage before and after cadaveric kidney transplantation.

It is possible that thoracic-duct drainage, a major but neglected immunosuppressive adjunct, can have an important impact on organ transplantation. If thoracic-duct drainage is started at the time of transplantation, the practicality of its use in cadaveric cases is greatly enhanced. With kidney transplantation, the penalty of not having pretreatment for the first organ is compensanted by the automatic presence of pretreatment if rejection is not controlled and retransplantation becomes necessary. The advantage of adding thoracic-duct drainage to conventional immunosuppression may greatly enhance the expectations for the transplantation of extrarenal organs, such as the liver, pancreas, heart, and lung. There is evidence that pretreatment with thoracic-duct drainage of patients with cytotoxic antibodies may permit successful renal transplantation under these otherwise essentially hopeless conditions. Exploration of the neglected but potentially valuable tool of thoracic-duct drainage seems to the authors to be highly justified in other centers.

Thoracic duct drainage in organ transplantation: will it permit better immunosuppression?

Thoracic duct drainage was added to conventional immunosuppression with azathioprine, prednisone and, sometimes, antilymphocyte globulin in 83 patients given cadaveric kidneys, including 65 primary graft recipients. The most effective use of thoracic duct drainage was for pretreatment. Optimal conditioning was at least four weeks duration, and when lymph drainage was this long, the incidence of rejection during the first three postoperative months was reduced to 4.5 per cent. Shorter pretreatment or institution of thoracic duct drainage contemporaneous with transplantation were less effective, but the one year results were still better than those with conventional immunosuppression alone. However, the advantage gained with thoracic duct drainage during the first year was diminished in all the treatment groups by graft losses in the second postoperative year. It was concluded that, without better maintenance therapy, the full value of temporary early lymphoid depletion procedures cannot be fully exploited.

/pdf/late-follow-up-after-thoracic-duct-drainage-in-cadaveric-2ckxl1vo3n.pdf

Late follow-up after thoracic duct drainage in cadaveric renal transplantation

1. Patients subjected to TDD prior to transplantation had a 4-yr graft survival rate of 65% compared to a comparably HL-A-matched group in which the survival rate was 35%9 2. Patients classified as non-responders to tissue antigens have a much higher graft retention rate than responders. Responders subjected to TDD have a 1 yr graft survival rate of 62% compared to a comparably HL-A-matched group with a survival rate of 28%. 3. Individuals with a positive crossmatch or receiving second or third transplants and subjected to TDD do much better than such individuals not subjected to TDD.

Preformed cytotoxic antibody in patients subjected to thoracic duct drainage.

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Preformed cytotoxic antibody in patients subjected to thoracic duct drainage.