Date of Completion

5-2-2016

Embargo Period

4-20-2016

Keywords

stem cell, skin graft, CD13, transplant

Major Advisor

Linda Shapiro

Associate Advisor

Kevin Claffey

Associate Advisor

Hector Aguila

Associate Advisor

Christine Finck

Associate Advisor

Pramod Srivastava

Field of Study

Cell Biology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The goal of transplantation is to implant healthy tissues or organs to successfully replace those that are damaged or defective. Currently allo-transplantation is almost universally prevented by immune mediated rejection without significant pharmacological intervention. Traditional methods of immune-suppression expose patients to undesirable risks and side effects, clearly necessitating more specific treatments that will mitigate immune responses to major and minor histocompatibility mismatches between the donors and hosts as well as concurrent inflammatory processes. Clinical trials of biologics targeting T and B cell pathways are ongoing; however, these agents often require combined treatments with other pharmacologics and still cause various adverse events. The alternate approach of establishing immune chimerism by concurrent donorderived hematopoietic cell infusion is promising, but requires a period of induction chemotherapy and has not been successful in some patients. Overexpression of cell surface molecules such as CD200 or CTLA-4 and PD-1 have also been shown to promote donor-specific immune tolerance, but these studies are still early in development. Here, we introduce a novel immune regulator, CD13. Exclusive modulation of CD13 enhanced survival of minor histocompatibility mismatched skin allografts as well as growth of embryonic stem cell-derived teratomas in wild type and CD13 null transgenic mice. Importantly, teratoma growth was identical in immunocompromised mice, implicating an immune mechanism underlying this phenomenon. While absence of CD13 in both grafts and hosts provided optimum results, lack of CD13 in graft tissue alone prevented rejection indefinitely (>100 days). Accepted allografts were associated with increased mast cell numbers but reduced mast cell degranulation, decreased CD8+ cytotoxic T cells and additional significant differences in immune cell profiles in the grafts as well as draining lymph nodes. Transient CD13 blockade in wild-type recipients with a CD13-specific monoclonal antibody also prolonged graft survival. Thus, targeting CD13 may provide an alternate or adjunct therapy to promote transplant survival.

Download
COinS