Delayed immune recovery after allogeneic hematopoietic stem cell transplantation (alloHSCT) is arguably the single greatest barrier to the successful use of this treatment modality.1  In this issue of Blood, Merindol et al dissect the phenotypic and functional patterns of T-cell recovery in recipients of partially HLA-matched unrelated donor umbilical cord blood (UCB).2 

While an effective treatment for selected malignant and nonmalignant disorders, alloHSCT is associated with a profound and prolonged immunodeficiency state. As a consequence, alloHSCT is associated with a high incidence of opportunistic infection. Furthermore, data suggest that a delay in immune recovery may also contribute the risk of relapse at least in some patient populations.3  It is already known that the recovery of antigen specific T cells after alloHSCT is dependent on donor and host factors, like HLA match, T-cell depletion of the allograft, degree of tissue damage from the conditioning regimen, and the development of acute graft-versus-host disease (GVHD).4  Based on studies in murine models, immune recovery after alloHSCT is characterized by an initial wave of thymic independent, peripherally expanded T cells that has a limited and skewed T-cell repertoire, with a second wave of thymic-educated donor HSC-derived T cells occurring months afterward, ultimately leading to the redevelopment of adaptive immunity in the transplant recipient.5,6  Studies in the human have proven vastly more problematic. Variables in the transplant recipient, such as differences in patient age, graft source, HLA match, tissue damage, viral infections, and severity of GVHD, and the absence of validated assays of immune reconstitution have hindered progress in the field. The one thing that is clear is the presence of lymphocytes or any specific T-cell subset after transplant is itself not equivalent to restoration of T-cell immunity.5 

Recent technologic advances have led to a better understanding of the T-cell response to pathogens and cancer. Detection of low frequency antigen-specific T cells is now possible using major histocompatibility complex (MHC) tetramer technology, intracellular cytokine staining of epitope-stimulated T cells, and IFN-γ ELISPOT assay for peptide-stimulated cells. In this study by Merindol et al the extent of CD8+ T-cell reconstitution was interrogated in 26 recipients of HLA-A2+ UCB at 1,2, 3, 6, 12, 18, 24, and 36 months after transplantation.2  Using the HLA-A2–restricted Melan-A26-35 A27L peptide (A2/Melan-A), which is one of the few preimmune T-cell repertoires that can be studied in humans,7  the authors observed a decline in the clonal diversity of Melan-A26-35–specific CD8+ T cells reaching its nadir at 3 months after transplantation. At 6 months, however, naive T cells emerged with increasing clonal diversity and polyfunctionality as measured in sorted tetramer-specific CD8+ T cells. Expectedly during the period of acute homeostatic proliferation after transplant, high frequencies of programmed death-1 (PD-1)–expressing CD8+ T cells were observed as clonal diversity declined. Interestingly, a higher frequency of PD-1+CD8+ T cells was associated with a higher risk of relapse.

However, in addition to providing us with a detailed characterization of the decline and restoration of T-cell subsets after umbilical cord blood transplantation, the current study by Merindol et al also unveiled a unique opportunity for analyzing and repairing the immune system. In this setting where 50% to 75% of patients receive UCB grafts that are mismatched at 2 HLA antigens,8,9  it follows that we can potentially “select for” a specific, preferred HLA antigen, such as HLA-A0201, regardless of whether it is matched or mismatched with the recipient. Perhaps this is a new raison d'etre for UCB! First, we already know that we can select UCB units with a “desired” HLA antigen—we have already done this to track UCB-derived T regulatory cells.10  Second, HLA-A0201 occurs with relatively high frequency in the general population (29.6% of Europeans, 12.4% African-Americans, 9.5% Asian-Pacific Islanders, and 19.4% of Hispanic haplotypes).11  Considering the myriad of HLA-A0201 based reagents for dissecting the immune response after alloHSCT, one could envision a new roadmap for designing and testing novel interventions for enhancing T-cell recovery—proof-of-concept studies initially in HLA-A2 transgenic mice followed by clinical testing of the most promising candidate strategies specifically in recipients of HLA-A0201+ UCB units that could occur at an unprecedented frequency. Studies could include the use of ex vivo–expanded T-progenitor cells, agents to enhance thymic function or protect/preserve thymus and lymph node architecture, in vitro priming to generate antigen-specific T cells specific for problematic viral pathogens like CMV, HHV6, BK, EBV, and adenovirus, or tolerance-inducing agents like T regulatory cells. The possibility of parallel studies in mouse and man and the capacity to enhance the proportion of patients transplanted with HLA A2+ alloHSC could dramatically alter the pace of discovery and allow us to overcome this last great barrier that limits the successful use of alloHSCT.

Conflict-of-interest disclosure: The authors declare no competing financial interests. ■

1
Barrett
 
J
Improving outcome of allogeneic stem cell transplantation by immunomodulation of the early post transplant environment.
Curr Opin Immunol
2006
, vol. 
18
 
5
(pg. 
592
-
598
)
2
Merindol
 
N
Champagne
 
MA
Duval
 
M
Soudeyns
 
H
CD8+ T-cell reconstitution in recipients of umbilical cord blood transplantation and characteristics associated with leukemic relapse.
Blood
2011
, vol. 
118
 
16
(pg. 
4480
-
4488
)
3
Parkman
 
R
Cohen
 
G
Carter
 
SL
, et al. 
Successful immune reconstruction decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation.
Biol Blood Marrow Transplant
2006
, vol. 
12
 
9
(pg. 
919
-
927
)
4
Gress
 
RE
Komanduri
 
KV
Einsele
 
H
Cooper
 
LJN
Lymphoid reconstitution and vaccines.
Biol Blood Marrow Transplant
2007
, vol. 
13
 
1 Suppl 1
(pg. 
17
-
22
)
5
Storek
 
J
Geddes
 
M
Khan
 
F
, et al. 
Reconstitution of the immune system after hematopoietic stem cell transplantation in humans.
Semin Immunopathol
2008
, vol. 
30
 
4
(pg. 
425
-
437
)
6
Wils
 
E-J
Cornelissen
 
JJ
Thymopoiesis following allogeneic stem cell transplantation: new possibilities for improvement.
Blood Rev
2005
, vol. 
19
 
2
(pg. 
89
-
98
)
7
Alanio
 
C
Lemaitre
 
F
Law
 
HK
Hasan
 
M
Albert
 
ML
Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies.
Blood
2010
, vol. 
115
 
18
(pg. 
3718
-
3725
)
8
Eapen
 
M
Rocha
 
V
Guillermo
 
S
, et al. 
Effect of graft source on unrelated donor heamatopoietic stem-cell transplantation in adults with acute leukemia: a retrospective analysis.
Lancet Oncol
2010
, vol. 
11
 
7
(pg. 
653
-
660
)
9
Brunstein
 
CG
Wagner
 
JE
Hoffman
 
R
Benz
 
EJ
Shattil
 
SJ
Furie
 
B
Cohen
 
HJ
Silberstein
 
LE
McGlave
 
P
Umbilical Cord Blood Transplantation.
Hematology: Basic Principles and Practice
2008
5th ed
New York, NY
Churchill Livingston
10
Brunstein
 
CG
Miller
 
JS
Cao
 
Q
, et al. 
Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.
Blood
2011
, vol. 
117
 
3
(pg. 
1061
-
1070
)