Try this (not so) trivial pursuit question: What do thebrain, the eyeballs and the testicles have in common?
Answer: All three, virtually alone among mammalianorgans, are immunologically privileged. That is, theantibodies and T lymphocytes which staff the immunesystem can't get in to defend these three sites againstpathogenic invaders.
So each of the three organs has to fend for itself. Braintissue has a blood-brain barrier to prevent unwantedmolecules from infiltrating. (See BioWorld Today, Oct.17, 1995, p. 1.)
As to just how the eye ball's anterior chamber, betweenlens and cornea, wards off invasive molecules, the jury isstill out. By what ways and means testicular tissue exertsits immune privilege was a stubborn secret until today.Now that jury has rendered a verdict _ though notbeyond reasonable doubt _ in today's Nature.
A paper titled "A role for CD95 ligand in preventing graftrejection" reveals how the testis destroys killer T cellsbefore they have a chance to destroy it. It's co-authoredby two Denver immunologists, Richard Duke of theUniversity of Colorado, and Donald Bellgrau, BarbaraDavis Center for Childhood Diabetes.
Between them, they demonstrate in vitro and in vivo thatthe ligand to a molecule called CD95, secreted in thetestes, prevents killer T cells in the blood from runningamok.
"When the T-cell receptor sees an antigen, it becomesactivated," Duke explained to BioWorld Today, "Andone of the things it does is put a lot of this CD95molecule on its surface, so it can be recognized as armedand dangerous." After the invasion is contained, headded, "the immune system has to control itself bygetting rid of activated cells. If it doesn't, it runs the riskof developing autoimmunities."
To exert this feedback control, Duke said, "the CD95ligand _ a.k.a. Fas ligand _ causes the now-redundantimmune cells to commit suicide by apoptosis.
"CD95 and Fas are synonyms," Bellgrau explained. "It isexpressed on the T-cell surface. Fas ligand is what bindsto, and neutralizes cells expressing Fas. The yin and yangof the interaction."
Animals that lack either CD95 or its ligand developautoimmune diseases that will kill them," Duke pointedout. Their symptoms, he observed, "look an awful lot likelupus or rheumatoid arthritis."
Testis Side-Steps Graft Rejection _ But How?
"For a long time," Duke continued, "it's been known thatthe testis is an immune-privileged site. Nobody reallyunderstood why, but we knew that it was so effective insuppressing immunity that you could graft tissue evenacross animal species into the testis."
He and Bellgrau set out to find a molecule they knew wasmade by Sertoli cells, which had an immune suppressiveeffect in tissue culture. Sertoli cells provide physical andnutritional support to the budding sperm cells within thetestes' tightly coiled seminiferous tubules.
By guesswork, they fingered the CD95 molecule as "apretty good candidate, based on the fact that messengerRNA encoding it had been found in the testes. "Weshowed very quickly," Duke said, "that in fact Sertolicells express the CD95 ligand in the testis, which allowstesticular tissue, or Sertoli cells alone, to be transplantedacross major histocompatibility barriers."
Fortunately, to confirm their guesswork, they didn't haveto construct a knockout mouse lacking CD95 ligandfunction. Instead, they found a naturally occurring Fas-ligand-minus rodent that displayed this autoimmuneeffect. As described in the Nature paper, "we simply tooktestis or isolated Sertoli cells from these mutant rodents,and transplanted them into normal animals, whichpromptly rejected them. But graft tissue from mice able toexpress the ligand was accepted by their normal butimmunologically mismatched peers."
The flip side of that experiment, Duke went on "is that,by putting normal testis into a mouse whose T cells lackthe ability to express CD95 ligand itself, those T cellswere able, as one would predict, to reject the graftperfectly fine."
"These findings," the Nature paper suggested, "indicatethat Fas ligand could be used to create immune-privilegedtissue for a variety of transplant uses."
First Candidate: Missing Insulin-Making Islet Cells
"Duke's background," co-author Bellgrau told BioWorldToday, "is in Fas/Fas ligand interactions in vitro. Mine isin autoimmunity in diabetes. So my lab did all thetransplantation experiments.
"What we want to do," Bellgrau said, "is cure diabetes."He proposes enlisting testis-generated CD95 ligand inthis mission. "The biggest problem with diabetes rightnow," he pointed out, "is that there are a lot of patientsout there who don't have any Islets of Langerhans [whichproduce insulin on demand] because they have beendestroyed by autoimmune disease.
"What's more, there are very few Islet donors out there,because of the chronic organ-shortage problemexperienced in all transplant situations." Bellgrau'sChildhood Diabetes Center aims to "find a way ofimplanting islets that don't have to come from humandonors. And the Sertoli cell's protective effects workacross species barriers."
Ergo, "we're excited by the possibility that maybe Fasligand could protect xenografts, perhaps from pigs intohumans. There's a whole technology under developmentfor that." (See BioWorld Today, Sept. 29, 1995, p. 1.)
Alternatively, Bellgrau suggests, "Just take therecombinant, soluble Fas ligand cloned in bacteria, anduse it as a drug," to subdue inflammation or makeimmunosuppressive regimens more graft-friendly. "Or,using a gene-therapy approach, one could insert theligand into a human tissue for transplant."
He describes Fas ligand as "this wonderful molecule,"resident on human chromosome 1, with a coding regionof 843 base pairs, expressing 281 amino acids.
Bellgrau's Center has a patent application pending, hesaid, "covering the use of Fas ligand as animmunosuppressant, basically as we described in thisNature paper." As for commercialization, "We've had anumber of dances with pharmaceutical and biotechcompanies, but no specific licensing agreement with anyof those to date." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.