Page 1172 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1136 PART NINE Transplantation

accessory cells, including CD4, CD8, and NK-cell populations, demonstrated through evaluation of single nucleotide tandem
on the outcome of transplantation remain unconfirmed. Whether repeats (short tandem repeats [STRs]) by using molecular analysis.
or not this is clinically significant, the ratio and quantity of cell Obviously, such studies are of no value in assessing engraftment
populations collected will be affected by changes in the cytokines after auto-(syngeneic)HSCT.
and chemokines, used singly or in combination, to mobilize Much of the emphasis in transplantation has been on myeloid
HSCs into peripheral blood for collection or to alter bone marrow engraftment because initial patient survival depends on recovery
products collected from patients and donors. of phagocytes and, to a lesser extent, platelets. Immune reconstitu-
tion, and in particular donor T-cell reconstitution, in patients
Purging of Cell Populations receiving HSCT is often hampered by older recipient age, dimin-
For auto-HSCT, postcollection attempts to purge tumor cells ished functional status of the thymus, cytokine milieu at the time
potentially contaminating the graft have not demonstrated a of transplantation, and posttransplantation immunosuppressive
survival advantage for the transplant recipient. T-cell depletion treatments. The thymus involutes rapidly after childhood, and in
of donor HSCs by various methods is an effective means of the older adult, it is only able to contribute a very small portion
reducing the incidence of aGvHD or cGvHD; but it increases to the mature T-cell compartment. The thymic tissue may be
the risk of graft failure, opportunistic infections, and relapse, damaged as a result of a myeloablative conditioning regimen,
effectively nullifying any advantage. Higher doses of HSCs, which or it can also be a target of alloreactive donor T cells mediating
can be achieved by the use of large quantities of PBSCs or by GvHD. As a result, restoration of the T-cell compartment in
combining marrow and PBSC components, will offset this risk patients is often slow, particularly for CD4 T cells, and may
of graft failure. Partial T-cell depletion, as opposed to maximal be at suboptimal levels for many months to over a year. This
T-cell depletion, may also reduce the risk of graft failure. Some situation, of course, endangers the ability of the patient to stave
centers are exploring posttransplantation T-cell add-back after off opportunistic infections, such as from the herpes family of
the acute inflammatory effects of the conditioning regimen have viruses and fungal pathogens. If donor T cells are provided in
resolved in an effort to maintain the GvT effect while still reducing the HSC inoculum, some reconstitution of the T-cell repertoire,
GvHD morbidity and mortality. mostly CD8 T cells, is provided by the mechanism of nonthymic
homeostatic expansion, although the level of diversity may be
Expansion of HSC Products limited. Experimentally, administration of cytokines, such as
Ex vivo expansion of UCB HSCs is one potential mechanism to interleukin-7 (IL-7), after HSCT, can enhance thymic function
offset the low cell dose and delayed hematological recovery after and help donor T-cell reconstitution. B-cell reconstitution, in
transplantation. However, no expansion technique has yet achieved contrast, is not that problematic in terms of the regeneration of
this goal, and such endeavors are complicated by the difficulty the immune repertoire, although the ability to actually respond
in identifying the pluripotent HSCs in comparison with lineage- effectively to an infection with antibody production may still
committed progenitor cells. Furthermore, it is likely that expansion depend on the availability of antigen-specific CD4 T cells.
techniques will result in T-cell depletion, resulting in the other Administration of Ig to patients with low IgG levels can prevent
complications described above. some of the infectious complications. Patients receiving HSCT
who are conditioned with myeloablative regimens usually attain
Hematological Recovery high levels of donor chimerism in their lymphoid compartment
HSC engraftment encompasses two concepts: (i) recovery of within a few months of transplantation. This often correlates
hematopoietic and immunological function and (ii) the rate at with the ability of alloreactive donor T cells, capable of mediating
which this recovery occurs. Delay in or failure of sustained GvHD, to target residual recipient HSC elements so that the
engraftment after myeloablative-conditioning regimen administra- primary source of de novo lymphoid reconstitution will be from
tion greatly increases treatment morbidity and cost. Engraftment the donor origin. By the same token, high donor chimerism is
failure can occur as a result of inadequate HSC quantity from also associated with a lower incidence of relapse of malignancy.
poor collection or loss in postcollection processing, inadequate
host support of the infused cells, posttransplantation events or CONDITIONING REGIMENS
medications, or HvG rejection (see Fig. 83.3). Engraftment failure
is a very rare complication of auto-HSCT and is most likely a Dose-Intensive and Reduced Intensity Chemotherapy
consequence of poor preservation of HSCs after collection. In The pretransplantation regimen is intended to accomplish two
allo-HSCT, the risk of engraftment failure is proportional to the goals: ablate the tumor and achieve adequate immunosuppression
donor HLA–miHA disparity, occurring more commonly in to allow donor engraftment. For auto-HSCT, only the dose-
unrelated donor transplants than in sibling donor transplants, sensitivity of the tumor being treated need be considered. Lower
and with HLA-mismatched transplants. Engraftment failure is dose, nonmyeloablative regimens are not used in auto-HSCT
also increased by T-cell depletion of marrow inoculum because because with such regimens, infusion of HSCs to reconstitute
of the loss of the GvH effect against residual host immune cells. marrow function would not be needed. Total body irradiation
Chimerism assessment is important in evaluating graft function (TBI) was initially used for conditioning of transplant recipients.
after allo-HSCT. A fall in PBSC counts could indicate HvG This modality achieves tumor cytotoxicity; treatment of sanctuary
rejection of the graft or early relapse after transplantation or sites of disease, such as the central nervous system (CNS) and
could result from GvHD or viral infection. Documentation of testes; and profound immunosuppression. TBI is usually combined
stable persistence of donor T cells in the recipient’s blood will in sequence with chemotherapy agents, such as cyclophosphamide
help discriminate between these possibilities. It is also important or etoposide. Busulfan-based regimens were developed as alterna-
that sustained lymphoid chimerism be demonstrated if DLI is tives to TBI for patients who had received prior dose-limiting
to be used in the treatment of disease relapse after transplantation. radiotherapy and to avoid the effects of TBI on growth and
The level of donor–host chimerism after allo-HSCT is best development in children. A review of several studies that compared