Page 1145 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 81 Concepts and Challenges in Organ Transplantation 1111

donor-type thymic DCs, with the result that developing T cells with mild, nonmyeloablative total body irradiation or costimula-
with antidonor specificity are deleted by negative selection. tory blockade with anti-CD154 and/or CTLA-4 Ig. When these
Full chimerism can be obtained rapidly through the ablation induction protocols are followed by BMT, the result is mixed
of the recipient’s marrow and immune system with high-dose chimerism (the continued survival of both donor and recipient
radiation and/or chemotherapy; in addition it can be induced hematopoietic progenitor cells). Animals that have undergone
more slowly by nonablative conditioning regimens, followed by these therapies have demonstrated durable tolerance to donor-type
the infusion of donor’s marrow to colonize the recipient com- allografts and have a much lower incidence of GvHD compared
pletely. This phenomenon paves the way for the onset of tolerance with full chimeras.
in the case of a subsequent SOT from the same donor. 64 In particular, the Massachusetts General Hospital (MGH)
As proof of concept, numerous patients have undergone suc- transplantation group showed in mouse and NHP models that
cessful BMT for hematological indications and have subsequently nonmyeloablative regimens could result in transient mixed
been successfully transplanted with a kidney from the same donor, chimerism with accompanying long-term transplantation toler-
without the requirement for increased immunosuppression. ance. Indeed, the same group has reported the long-term follow-up
It is important to highlight that in all these cases, the use of of human recipients, who underwent combined HLA-matched
BMT was justified on the basis of the need for treatment of bone marrow and kidney transplantation for end-stage renal
hematological malignancies. disease with or without multiple myeloma. 66,67
An alternative approach to achieving full chimerism and hence
tolerance to donor alloantigens while avoiding GvHD or engraft- Regulatory T Cells
ment syndrome, in HLA-mismatched unrelated stem cell/renal There is now abundant evidence for the existence of populations
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transplant human recipients has been reported. Results were of regulatory lymphocytes with the ability to suppress immune
achieved with the introduction of a mobilized cellular product responses by other leukocytes (Chapter 18). Tregs can be divided
enriched for tolerogenic graft facilitating cells (FCs) as well as into two populations: thymic-derived naturally occurring
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HSCs and T cells (the treatment with HSCs in combination with CD25 CD4 cells (tTregs) and induced Tregs or iTregs that are
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FCs is termed FCRx) rather than just bone marrow graft alone. either differentiated from CD25 CD4 nonregulatory cells or
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These bone marrow–derived FCs, which are CD8 but do not expanded from CD25 CD4 cells in response to antigen. Expres-
express a TCR, potently enhance engraftment of allogeneic HSCs sion of the transcription factor FOXP3 is essential for the
in conditioned recipients. FCs are composed predominantly of development and function of Tregs; however, tTregs and iTregs
a plasmocytoid precursor DC subpopulation, induce the genera- differ in origin, antigen experience, methylation patterns of
tion of antigen-specific Tregs in vitro and in vivo, and have been FOXP3, and suppressive mechanisms. Both tTregs and iTregs
found to effectively prevent GvHD in mice. In the first phase of have been demonstrated to play important roles in transplant
this single-center clinical study, eight HLA-mismatched kidney tolerance.
transplant recipients were treated with FCRx and nonmyeloabla- tTregs develop within the thymus under the direction of FOXP3
tive conditioning during the peritransplantation period. One and have a critical role in limiting immune responses to self
year later, five recipients exhibited durable macrochimerism with antigens, as demonstrated by experimental models where mice
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no incidence of GvHD or engraftment syndrome, and were depleted of CD25 CD4 cells subsequently develop inflammatory
immunosuppression-free—that is, these patients were clinically bowel disease (IBD) and widespread autoimmune phenomena.
operationally tolerant. In vitro studies indicated that chimeric Mutation of FOXP3 in humans is responsible for immune
donor lymphocytes were tolerized to the recipient, and a sig- dysfunction/polyendocrinopathy/enteropathy/X-linked (IPEX)
nificant increase in the CD4 Treg/T effector cell population ratio syndrome (Chapter 35). There is evidence for the involvement
was observed in these patients when compared with those who of Tregs in the downregulation of immune responses to tumors
had lost chimerism. The ability to establish high levels of donor and chronic infections, as well as allogeneic transplants. 70
multilineage chimerism in haploidentical and highly mismatched Many strategies exist for the in vivo or ex vivo generation
unrelated donor–recipient pairs without the development of and/or expansion of Tregs. The most common in vivo approaches
GvHD through the use of novel cellular therapies could have are based on the fact that stimulation with anti-CD3 and
exciting therapeutic implications for disorders for which HSC anti-CD28 in the presence of high concentrations of IL-2
transplantation can provide a “functional cure,” including stimulates proliferation and that exposure to antigen increases
inherited metabolic disorders, hemoglobinopathies, and auto- Treg frequency and/or potency by either expanding tTregs or
immune disease, as well as in solid organ transplantation. inducing the generation of iTregs from cells that do not originally
Longer-term follow-up data on these initial patients as well as possess regulatory activity. There is a large body of data dem-
data from the enrollment of additional patients into this protocol onstrating that ex vivo expanded Tregs can protect allografts
continue to be encouraging. A phase III multicenter clinical trial from rejection. 56,71
is planned. Transplant recipients are treated with diverse immunosup-
pressive drug combinations, which may have a different impact
Mixed Chimerism on Tregs. As mentioned in the previous section, it has been
A promising approach is the induction of mixed hematopoietic demonstrated that CNIs, in particular cyclosporine, are detri-
chimerism, which can be achieved in experimental models with mental to Tregs, whereas the mTOR inhibitor rapamycin was
far less toxic induction therapy. Nonmyeloablative conditioning shown to be beneficial to Tregs both in terms of in vivo generation
regimens have been applied in the clinical setting in patients and function in mouse models and in vitro cultures of human
who develop renal failure as a consequence of multiple myeloma. Tregs. Adoptive transfer of a low number of alloantigen-specific
Further refinements of such protocols are being explored in Tregs under a cover of low-dose rapamycin was found to be
experimental models. Examples of these include either a combina- capable of inducing long-term survival of heart transplants in
tion of depleting anti-CD4 and anti-CD8 antibodies together an unmanipulated host, an outcome otherwise difficult to obtain. 72