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Toll-like Receptors and Allograft Rejection

We read with interest the article from Palmer and colleagues (1) demonstrating that recipients heterozygous for a mutation in the toll-like receptor (TLR) 4 gene had reduced acute allograft rejection after lung transplantation. The authors also demonstrated that mutations in the allograft had no impact. It would be of interest to investigate whether transplant recipients with the mutated TLR4 gene (Asp299Gly or Thr399Ile) had defects in adaptive immune function after transplantation in addition to reduced rejection rates. Do lymphocytes from these patients demonstrate reduced interferon- production in response to donor antigen? Is there a reduction in the number of donor-specific antibodies in these recipients? These are important questions as work in experimental models has demonstrated that mice that are deficient in an important TLR signal adaptor protein, MyD88, have impaired priming and production of helper T cell type 1 immune responses in infectious and transplant models (2, 3). In our work using TLR2-, TLR4-, and MyD88-deficient animals, we demonstrated that allograft rejection of HY incompatible skin allografts was largely abrogated in the absence of MyD88 (2). TLR2-deficient animals had a marginal delay, but TLR4 recipients did not manifest reduced acute rejection, in contrast to the work by Palmer and colleagues (1). Furthermore, rejection could be reestablished by restoring MyD88 signaling in either the donor or the recipient. Clearly, there are likely to be large differences between an experimental model and a clinical study. It would be of interest to investigate whether the TLR4 mutation (or any other TLR mutation) impacts other types of solid organ transplantation.

Daniel R. Goldstein and Bethany M. Tesar

Yale University School of Medicine New Haven, Connecticut

FOOTNOTES

Conflict of Interest Statement: D.R.G. and B.M.T. have no declared conflict of interest.

REFERENCES

1. Palmer SM, Burch LH, Davis RD, Herczyk WF, Howell DN, Reinsmoen NL, Schwartz DA. The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med 2003;168:628–632.[Abstract/Free Full Text]
2. Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest 2003;111:1571–1578.[CrossRef][Medline]
3. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2001;2:947–950.[CrossRef][Medline]

From the Authors:

We thank Drs. Goldstein and Tesar for their comments regarding our study (1). Goldstein and colleagues recently observed that skin allograft rejection did not occur in mice with targeted disruption of MyD88, but did occur in those with disruption of toll-like receptor (TLR) 2 or TLR4 (2). In contrast, we found decreased acute rejection in lung transplant recipients heterozygous for either of two mutations in TLR4 previously associated with endotoxin hyporesponsiveness (3). There are likely several important explanations for the differences between their animal model and our clinical study. First, environmental exposure directly into the allograft makes clinical lung transplant unique. Inhalational exposure to air pollution (including endotoxin), infectious agents (such as gram-negative bacteria), and other noxious toxins occurs on a regular basis after lung transplantation. As a result, TLR4 may be of particular importance in the initiation of innate and adaptive immune responses after lung transplantation. Genetic differences in TLR4 signaling, therefore, might exert a greater influence on posttransplant rejection in lung transplant as compared with other organs. Second, in contrast to the murine model used by Dr. Goldstein, in which mice were identical at the major histocompatibility (MHC) loci, almost all human lung allograft recipients have multiple MHC mismatches with the donor (4). MHC matching is not performed because of short cold ischemic times tolerated by lung allografts. The absence of a significant effect with the TLR4 disruption in the murine model does not address the impact of impaired TLR4 signaling in the setting of multiple MHC differences. Finally, we were interested to see that in the study by Goldstein and colleagues (2) there was a trend toward decreased skin allograft rejection in mice with disruption of TLR4 (p = 0.13), with one TLR4^–/–-recipient mouse demonstrating indefinite skin graft survival, providing some experimental support for our results.

We agree that allograft rejection is a complex biological response, and further study of the cellular and humoral response to the allograft in lung transplant recipients with the 299/399 polymorphisms is critical. We look forward to pursuing additional studies that elucidate the mechanisms by which innate and adaptive immunity interact in the setting of human organ transplantation. Further investigation into the immunogenetics of the alloimmune response may greatly enhance our ability to prevent and treat clinical rejection. Ultimately, both our clinical study and the animal work suggest an important and previously unrecognized role for innate immunity in the development of allograft rejection.

Scott M. Palmer, Lauranell H. Burch and David A. Schwartz

Duke University Medical Center Durham, North Carolina

FOOTNOTES

Conflict of Interest Statement: S.M.P. and L.H.B. have no declared conflict of interest. D.A.S. has a patent pending on toll-4 assay and has no other declared conflict of interest.

REFERENCES

1. Palmer SM, Burch LH, Davis RD, Herczyk WF, Howell DN, Reinsmoen NL, Schwartz DA. The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med 2003;168:628–632.
2. Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest 2003;111:1571–1578.
3. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000;25:187–191.[CrossRef][Medline]
4. Quantz MA, Bennett LE, Meyer DM, Novick RJ. Does human leukocyte antigen matching influence the outcome of lung transplantation? An analysis of 3,549 lung transplantations. J Heart Lung Transplant 2000;19:473–479.[CrossRef][Medline]

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