Thyroid hormone: relevance to xenotransplantation

Abstract

Background: It has been well documented that the level of serum/plasma free triiodothyronine (fT3) falls rapidly following brain death or during certain surgical procedures, for example, heart surgery carried out on cardiopulmonary bypass. The level in patients following cardiopulmonary bypass usually recovers within 2 days.

Methods: We have measured serum fT3 in healthy naïve baboons (n = 31), healthy naïve monkeys (n = 5), and after pig-to-baboon heterotopic heart xenotransplantation (xenoTx) (Group 1, n = 9), orthotopic liver xenoTx (Group 2, n = 10), artery patch xenoTx (Group 3, n = 9), and in monkey-to-monkey heterotopic heart alloTx (Group 4, n = 5).

Results: The mean level of fT3 in healthy naïve baboons was 3.1 ± 0.9 pg/ml and in healthy naïve monkeys was 2.6 ± 0.3 pg/ml. Following pig heart, liver, and artery patch xenoTx and monkey heart alloTx, there was an immediate rapid fall in fT3 level. Recovery of fT3 was more rapid in Groups 3 and 4 than in Groups 1 and 2. In Group 1, within 4 days fT3 had recovered, but only to the lower limit of normal range, where it remained throughout follow-up (for up to 42 days). In Group 2, no recovery was seen during the 7 days of follow-up. In immunosuppressed baboons with pig patch grafts that received IL-6R blockade (n = 2), the fT3 tended to rise higher than in those that received no IL-6R blockade (n = 6).

Conclusions: Following operative procedures, there is a dramatic fall in serum fT3 levels. The persistent low level of fT3 after pig heart and liver xenoTx may be associated with a continuing inflammatory state. We suggest that consideration should be given to the replacement of T3 therapy to maintain normal fT3 levels, particularly in nonhuman primates undergoing orthotopic pig heart or liver xenoTx.

Keywords: euthyroid sick syndrome; genetically engineered pigs; inflammation; nonhuman primates; thyroid hormone; xenotransplantation.

Figure 1

Changes in fT3 levels in nonhuman primate recipients following (A) heterotopic heart grafts (xeno or allo) or (B) orthotopic liver xenotransplantation (Tx). (A) In both xeno- and allo-heart recipients, there was a rapid fall of fT3 level to 0.9pg/mL (in xenoTx) and 1.1pg/mL (in alloTx), respectively, within 24 hours (p<0.01; p<0.05, respectively). Within 4 days after Tx, the level of fT3 had recovered after heart xenoTx to just below the lower limit of normal range, but to a higher level after alloTx. Reductions in the level of fT3 were observed in baboons that were suspected of developed a systemic infection, or had histopathological features of a thrombotic microangiopathy. (B) After liver xenoTx, there was a rapid fall of fT3 to 0.3pg/mL within 4hours with little recovery during the 7 days of follow-up. The horizontal lines indicate the normal range of fT3 in healthy naïve baboons.

Figure 1

Changes in fT3 levels in nonhuman primate recipients following (A) heterotopic heart grafts (xeno or allo) or (B) orthotopic liver xenotransplantation (Tx). (A) In both xeno- and allo-heart recipients, there was a rapid fall of fT3 level to 0.9pg/mL (in xenoTx) and 1.1pg/mL (in alloTx), respectively, within 24 hours (p<0.01; p<0.05, respectively). Within 4 days after Tx, the level of fT3 had recovered after heart xenoTx to just below the lower limit of normal range, but to a higher level after alloTx. Reductions in the level of fT3 were observed in baboons that were suspected of developed a systemic infection, or had histopathological features of a thrombotic microangiopathy. (B) After liver xenoTx, there was a rapid fall of fT3 to 0.3pg/mL within 4hours with little recovery during the 7 days of follow-up. The horizontal lines indicate the normal range of fT3 in healthy naïve baboons.

Figure 2

Changes of fT3 levels in baboon recipients following (A) pig artery patch (with or without immunosuppressive therapy [IS]), or (B) pig artery patch xenotransplantation (with or without receiving IL-6R blockade). (A) In immunosuppressed baboon recipients of pig artery patch grafts, mean fT3 level markedly decreased from 3.6pg/mL pre-Tx to 1.1pg/mL (p<0.01) within 24h. Within 4 days, it had recovered to within the normal range (mean 2.4pg/mL) where it remained through follow-up. In the one baboon that received no immunosuppressive therapy, the fT3 level tended to remain rather lower during follow-up (though not significantly different). (B) A rapid fall and recovery of fT3 was observed after pig artery patch Tx in immunosuppressed baboons, but the fT3 levels recovered more rapidly in baboons receiving IL-6R blockade. When IL-6R blockade was not administered, the recovery of fT3 tended to be slower. The horizontal lines indicate the normal range of fT3 in healthy naïve baboons.

Figure 2

Changes of fT3 levels in baboon recipients following (A) pig artery patch (with or without immunosuppressive therapy [IS]), or (B) pig artery patch xenotransplantation (with or without receiving IL-6R blockade). (A) In immunosuppressed baboon recipients of pig artery patch grafts, mean fT3 level markedly decreased from 3.6pg/mL pre-Tx to 1.1pg/mL (p<0.01) within 24h. Within 4 days, it had recovered to within the normal range (mean 2.4pg/mL) where it remained through follow-up. In the one baboon that received no immunosuppressive therapy, the fT3 level tended to remain rather lower during follow-up (though not significantly different). (B) A rapid fall and recovery of fT3 was observed after pig artery patch Tx in immunosuppressed baboons, but the fT3 levels recovered more rapidly in baboons receiving IL-6R blockade. When IL-6R blockade was not administered, the recovery of fT3 tended to be slower. The horizontal lines indicate the normal range of fT3 in healthy naïve baboons.