Human Upper Extremity (Hand and Forearm) Allotransplantation

Overall Goal

To establish hand transplantation as a safe and effective reconstructive strategy for the treatment of upper extremity amputations.

Specific Aim

To reduce the risk of rejection and enable allograft survival while minimizing the requirement for long term high dose immunosuppression.

For this purpose, we propose to utilize the "Pittsburgh Protocol", which is an immunomodulatory strategy that has been implemented in solid organ transplants at UPMC. Early results in living related liver and kidney patients have confirmed that this protocol provides the means to allow graft survival with minimization of maintenance immunosuppression and even allows weaning of some patients from long-term immunosuppression.We hypothesize that a similar protocol can enable graft survival in highly immunogenic composite tissue allografts like hand transplants while reducing the number,dosing and/or frequency of immunosuppressive drugs associated with serious adverse effects.

Suitable candidates will be identified via patient information brochures and via advertisements directed at upper limb amputees. For this purpose, a web-page will be constructed for free access by interested individuals. This website will be accessible through standard search engines. Interested potential subjects will be instructed to contact the investigator for an appointment. At the time of appointment, candidates will be first requested to complete a screening consent form (SCF) before undergoing further evaluation/medical screening procedures. The SCF includes a written consent to obtain PHI of the candidate. When the candidate visits UPMC he will undergo a consultation with the PI who will perform a thorough clinical assessment and explain in detail the treatment options, risks and benefits of the procedure. Candidates will be requested to complete a screening consent at this stage. Appropriate subjects will then undergo further medical screening procedures that include a number of examinations and investigations to determine their candidacy for hand transplantation. Prospective recipients who are selected based on results of screening procedures will be invited to review and sign the full informed consent form prior to being wait-listed for the procedure.

The screening tests include:

History and physical exam, including height and weight Urine pregnancy test for all female subjects of childbearing potential Complete blood count, differential, reticulocyte count, platelet count ABO type Liver function tests including SGPT or SGOT, serum bilirubin (total and direct), total protein, albumin, alkaline phosphatase and GGT, PT, PTT with INR Serum electrolytes and renal function panel to include the following: sodium, potassium, chloride, carbon dioxide, calcium, phosphorus, magnesium, glucose, creatinine and BUN Urinalysis and creatinine clearance test to determine GFR Infectious disease studies: HIV antigen, HTLV I-II antibody, antibodies to HIV 1 and 2, hepatitis C virus, syphilis, hepatitis B core antibody, and hepatitis B surface antigen titers are required Infectious disease titers: CMV, EBV, HSV, toxoplasmosis and VZV (IgG and IgM when indicated) Pulmonary function tests, including DLCO2 Chest X-ray EKG and MUGA scan or echocardiogram for determination of cardiac ejection fraction Sinus X-ray (if clinically indicated) CT scans (CT Angiography)/MRI studies (Functional MRI, Skeletal MRIs of hand/hips) as indicated by medical history and physical examination Ophthalmologic examination Dental consult Psychiatric evaluation

• Gorantla VS, Schneeberger S, Moore LR, Donnenberg VS, Zimmerlin L, Lee WP, Donnenberg AD. Development and validation of a procedure to isolate viable bone marrow cells from the vertebrae of cadaveric organ donors for composite organ grafting. Cytotherapy. 2012 Jan;14(1):104-13. Epub 2011 Sep 12.
• Gorantla VS, Brandacher G, Schneeberger S, Zheng XX, Donnenberg AD, Losee JE, Lee WP. Favoring the risk-benefit balance for upper extremity transplantation--the Pittsburgh Protocol. Hand Clin. 2011 Nov;27(4):511-20, ix-x. Review.
• Ravindra KV, Gorantla VS. Development of an upper extremity transplant program. Hand Clin. 2011 Nov;27(4):531-8, x. Epub 2011 Oct 6.
• Lovasik D, Foust DE, Losee JE, Lee WP, Brandacher G, Gorantla VS. Helping hands: caring for the upper extremity transplant patient. Crit Care Nurs Clin North Am. 2011 Sep;23(3):505-17. Review.
• Schneeberger S, Gorantla VS, Brandacher G, Zeevi A, Demetris AJ, Lunz JG, Metes DM, Donnenberg AD, Shores JT, Dimartini AF, Kiss JE, Imbriglia JE, Azari K, Goitz RJ, Manders EK, Nguyen VT, Cooney DS, Wachtman GS, Keith JD, Fletcher DR, Macedo C, Planinsic R, Losee JE, Shapiro R, Starzl TE, Lee WP. Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression. Ann Surg. 2013 Feb;257(2):345-51. doi: 10.1097/SLA.0b013e31826d90bb.

Donor Selection Criteria

Brain dead donors who have met the criteria for Determination of Death will be selected by the hand transplant team in conjunction with the CORE (Center for Organ Recovery and Education), the organ procurement agency (OPO) for Pittsburgh and covers Pennsylvania, New York and West Virginia. The mandatory requirements are family consent for limb donation, stable donor (does not require excessive vasopressors to maintain blood pressure), age between 18 to 55 years, limb matched for size with recipient, same blood type as recipient, negative cross-match, and importantly accurately matched for gender, skin tone and race (may be relative requirement depending on recipient consent).

Recipient Selection Criteria

Recipients will be selected from a population of subjects with upper limb loss. Recipients may be male or female and of any race, color or ethnicity. Inclusion criteria for the study: 1) Age (>18 years <60 years): Recipients <18 years of age are excluded due to limitations of giving full informed consent and the potentially increased risk of lymphoproliferative disorder in a younger population. Once hand transplantation and in particular the strategy for minimizing immunosuppression has proven to be efficacious and safe, the restrictions with regard to recipient age may be relaxed. 2) No serious co-existing medical (coronary artery disease, diabetes) or psycho-social problems (including alcoholism, drug abuse). 3) Must be negative for malignancy (for 10 years) or HIV (at transplant). 4) Negative crossmatch with donor. 5) Negative pregnancy test in female recipient of child bearing potential and consent to use reliable contraception for at least one year following transplantation. 6) Consent to cell collection, storage, and bone marrow infusion as part of the treatment regime. 7) Amputation may be recent (acute injury) or remote (patient may have undergone rehabilitation with prostheses).

• ARMED FORCES INSTITUTE OF REGENERATIVE MEDICINE (AFIRM)
• U.S. Army Medical Research and Materiel Command
• San Antonio Military Medical Center