Stable Mixed Chimerism and Tolerance of Vascularized Composite Allografts via Bcl-2 Inhibition
Abstract
Stable Mixed Chimerism and Tolerance of Vascularized Composite Allografts via Bcl-2 Inhibition Initiating Principal Investigator (PI): Curtis L. Cetrulo, Jr., M.D., FACS, FAAP; Partnering PIs: Tatsuo Kawai, M.D., Ph.D.; Alexandre G. Lellouch, M.D.; Co-Investigator: Gilles Benichou, Ph.D. The recent wars in Iraq and Afghanistan have resulted in >1,500 amputations in wounded Warriors, and approximately 500 have suffered multiple extremity amputations. Of 4,000 or so facial injuries, around 50 were catastrophic. These statistics demonstrate the growing challenge of modern warfare, in which improvements in body armor have reduced the number of fatalities in the field but, conversely, reflect the limitations of conventional reconstructive surgery in restoring our Service Members to health and wholeness. More importantly, the number of civilians with similar injuries resulting in limb loss or devastating craniofacial injuries is much greater – of 2 million people living with limb loss, more than 185,000 amputations are performed annually; of 3 million facial injuries presenting to the emergency room each year, estimates suggest that 0.5% (15,000) are considered catastrophic, and if just 1% (of the 15,000) are candidates for face transplantation, that translates to 150 new cases every year. The immense benefit of hand/face transplantation (i.e., vascularized composite allografts, VCAs) in restoring both the military and civilian populations has since been demonstrated successfully in more than 115 hand and 43 face VCA cases worldwide. There are two major limitations to wide application of VCA: immune rejection phenomenon (acute/chronic rejection and the consequences of lifelong immunosuppression) and organ preservation technology. Despite the use of potent immunosuppressive therapy, acute rejection of the VCA occurs in up to 90% of patients, most of whom experience at least one episode within the first year post- transplantation, and almost 60% develop multiple episodes. To prevent loss of the VCA, increased immunosuppression is required, resulting in additional morbidity. The mixed chimerism approach is the only successful strategy reported to induce immune tolerance in humans. In parallel, the extreme difficulty in finding matching donors is in stark contrast to solid organ transplants (e.g., kidneys, lungs, heart) in which the matching of donors and recipients is paramount to the longevity and function of both the transplant and patient. In fact, the matching of size, skin color, and gender currently take precedence in VCA. Moreover, VCAs are ethically, legally, and medically required to be taken from deceased donors (unlike for kidney and liver transplants). In turn, these requirements translate to a severe limitation in the potential number of VCA donors within the geographic vicinity of a patient awaiting a limb/face transplant. Once again, extending the preservation duration of donor tissues from a few hours to a few days would reduce the logistic limitations and enable matching across the entire U.S. instead of regionally, as is currently possible. Additionally, the extension of tissue viability may be applied to related fields, such as trauma, in order for amputated body parts to be recovered and preserved so that the patient can be stabilized before definitive surgery. Our group was the first to test a tolerant protocol in VCA in non-human primates. Nevertheless, this has been hampered by induction of only limited chimerism with the current conditioning regimen and the occurrence of acute rejection during the delayed period preventing the chimerism and occurrence of post-transplant lymphoma disease after BMT. Severe myelosuppression associated with the conditioning regimen required for engraftment of donor hematopoietic stem cells also makes this approach difficult to be used in routine clinical practice. However, Kawai’s group has recently developed a novel nontoxic conditioning regimen in NHPs
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210959
Entities
People
- Alexandre G Lellouch
Organizations
- Massachusetts General Hospital
- United States Army