Inducing Tolerance for Hand Transplants with Stem Cells

Curtis L. Cetrulo, Jr., MD,
Head of the Hand Transplantation
Service at Massachusetts
General Hospital

Massachusetts General Hospital (MGH) investigators have made an important step towards greater availability of hand transplants, face transplants and other transplants involving multiple types of tissue, and stem cells play an important role. Hand, face and soft tissue transplants are collectively known as vascularized composite allografts, or VCAs. A VCA transplant is one that involves transplantation of multiple tissue types: muscle, bone, nerves and skin. They are most frequently used to replace amputated hands and arms, and to repair severe facial injuries.

In recent publication in the American Journal of Transplantation (1), our team describes how a procedure developed at the MGH to induce immune tolerance to organ transplants has also succeeded in an animal model of VCAs. Transplantation of donor hematopoietic stem cells - either several months before or simultaneous with the limb transplant - allowed the animals to accept VCAs from immunologically-mismatched donors.

Although VCA transplants offer recipients significantly improved quality of life, they come with a price. Currently, patients who undergo a VCA transplant must take immune suppressing drugs for the rest of their lives to prevent graft rejection. These drugs leave patients more vulnerable to infection and have numerous long-term side effects. If the immune system of the transplant recipient could be induced to accept the donor tissue, it would greatly reduce the risks of the surgery.

A personal view of the new procedure is offered by Curtis L. Cetrulo, Jr., MD, senior author of the current study: "The need for lifelong immunosuppression to prevent graft rejection is the most important challenge in this type of procedure, since most potential VCA recipients are young and would face increased risks of infection, diabetes or kidney problems, and even some types of cancer over many years."

"Bringing immunologic tolerance to hand and face transplantation would result in a paradigm shift in the way we will be able to treat the horrific injuries our service members are sustaining in the current military conflicts in Iraq and Afghanistan, as well for the types of blast-injury extremity loss seen in the Boston Marathon bombing. Tolerance would give us a unique tool - a real game changer - with which to help these patients. Importantly, a number of different stem cell sources - both adult and perinatal - may provide the final pieces of this puzzle."

The MGH is a world leader in the development of tolerance-inducing protocols. Several decades of research led by David H. Sachs, MD, founder and scientific director of the MGH Transplantation Biology Research Center (TBRC), led to a protocol in which transplant patients receive both the needed organ and bone marrow from a living donor, producing a state called mixed chimerism, in which the patient's immune system contains both donor and recipient elements.

A number of patients have received kidney transplants using versions of the protocol pioneered at MGH, and were subsequently able to discontinue immunosuppressive drugs. Most of these patients have been able to remain off immunosuppressive medications long term, some for more than a decade.

The current VCA study was designed to test whether a similar protocol could induce tolerance to VCAs from immunologically mismatched donors in an animal model. An additional challenge is posed by the fact that skin, an essential part of a VCA, carries what could be considered its own immune system, making its acceptance by a recipient's immune system particularly problematic. In several previous attempts to induce VCA tolerance, bone and muscle tissue were accepted but the skin was rejected and eventually separated from the underlying tissue.

Building on previous TBRC animal studies, the researchers tested whether combining bone marrow transplantation with VCA could induce chimerism and tolerance. In the first phase of the study, four recipient animals received bone marrow transplants from immunologically mismatched donors in advance, allowing time to confirm that chimerism had been established before the VCA procedure - involving transplantation of components of a hind limb from the same donor - was carried out three to five months later. Even though the recipients received no immunosuppression after the transplant procedure, all animals accepted the transplant with no sign of rejection.

Since pretransplant induction of chimerism would not be practical for hand or face transplants from deceased donors, the researchers next tested VCA surgery conducted simultaneously with the bone marrow transplantation to induce tolerance in two recipient animals. The immune systems of the animals were conditioned prior to the procedure. Chimerism was successfully induced in both recipients, and overall results were the same as in the other group - immune tolerance of all components of the VCA with no evidence of rejection throughout the follow-up period, which for one recipient was more than 480 days.

Since the availability of human cadaver tissues cannot be precisely predicted, the MGH team is exploring two approaches to the issue of timing the procedures. In one, the patient begins immune conditioning as soon as a donor is identified and the patient receives a simultaneous transplant of VCA and bone marrow from the donor. In the second, the patient receives the VCA first with conventional immunosuppression, and then months later is conditioned to receive the bone marrow transplant. This second protocol is currently in clinical trials for organ transplants. However in the case of VCAs from deceased donors, any donor bone marrow would have to be collected at the same time that the transplant tissues are collected.

In addition, our group is investigating the use of other stem cell types that may make the procedure more effective. "Perinatal stem cells of various phenotypes - for example, mesenchymal stem cells or MSCs - may provide an effective adjunct to our protocol for inducing chimerism and make the approach both safer and more efficient." An advantage of MSC from perinatal tissues is that they can be stored in cryogenic banks and are always available at the time of need.

Curtis L. Cetrulo, Jr., MD, is the head of the Hand Transplantation Service in the MGH Division of Plastic and Reconstructive Surgery. He is affiliated with Harvard Medical School. Dr. Cetrulo received his MD from Tufts Medical School and served residencies at both Lahey Clinic and Long Island Plastic Surgical Group, followed by a Fellowship at California Pacific Medical Center. He is the lead author of the recent MGH study on induced immunologic tolerance for vascularized composite allografts (VCAs) from immunologically mismatched donors.

Reference

1. DA Leonard, JM. Kurtz, C Mallard, A Albritton, R Duran-Struuck, EA Farkash, R Crepeau, A Matar, BM Horner, MA Randolph, DH Sachs, CA Huang, & CL Cetrulo Jr.
   Vascularized Composite Allograft Tolerance Across MHC Barriers in a Large Animal Model
   American Journal of Transplantation 2014; 14(2):343-355. DOI:10.1111/ajt.12560