PERSPECTIVE
in the United States, with fewer antigenic differenc-
High interleukin-10 secretion
A/A
genotype No or mild GVHD D
Better survival
T-cell tolerance
Donor T cell
Recipient antigen-presenting cell
L interleukin-10
Low i t l ki 10 secretion
ti
C/C
Severe GVHD
genotype
Worse survival
Donor T cell
Recipient antigen-presenting cell
T-cell activation and expansion
Figure. Effects of Favorable and Unfavorable Interleukin-10 Genotypes
on the Risk of Graft-versus-Host Disease (GVHD) and Survival of Recipients.
immunosuppressive-drug regimen and the rate
at which the drugs are tapered. Clinical investiga-
tors will need to consider the interleukin-10 geno-
type as one of the factors according to which they
stratify patients for trials testing new strategies of
prophylaxis against GVHD.
The study by Lin et al. did not analyze cytokine
gene polymorphisms in transplants from unrelat-
ed volunteer donors. The morbidity and mortality
associated with acute GVHD are greater among re-
cipients of such transplants than among recipients
of transplants from HLA-identical siblings. It is not
yet clear whether interleukin-10 genotypes will be
important among recipients of transplants from un-
related donors, but the possibility is intriguing. For
example, the relatively low rate of GVHD after trans-
plants from unrelated donors in Japan has often
been ascribed to the more homogeneous gene pool
in that island nation as compared with the gene pool
Insulin-like Growth Factors and the Basis of Growth
Ron G. Rosenfeld, M.D.
Growth in any species is an extraordinarily com-
plex process, but growth in humans is character-
ized by a number of unique features. These include
dramatic fetal growth (the most rapid phase of hu-
2184
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Copyright 2003 Massachusetts Medical Society. All rights reserved.
A Protective Gene for Graft-versus-Host Disease
es in both HLA and minor histocompatibility pro-
teins. But the frequency of the favorable interleu-
kin-10 allele is approximately 70 percent among
Japanese people, as compared with 23 to 24 percent
among North Americans. This relatively high prev-
alence of the protective interleukin-10 genotype may
in part contribute to the lower rate of GVHD in Ja-
pan. Since the relatively high degree of antigenic
disparity between an unrelated donor and the recip-
ient may override a protective effect of the favorable
IL10 gene after stem-cell transplantation, we must
await additional data before coming to any firm con-
clusions.
A favorable interleukin-10 genotype could also
have a downside for patients with hematologic can-
cers: GVHD is closely associated with a beneficial
graft-versus-leukemia effect, which occurs when
donor T cells recognize foreign histocompatibility
antigens on cancer cells and kill them. If increased
production of interleukin-10 induces tolerance to
these antigens in donor T cells, they may fail to erad-
icate residual cancer. Lin et al. did not report the re-
lapse-related mortality among their patients an
issue that will require further study.
As we gain a better understanding of the molec-
ular mechanisms involved in the development of
GVHD, we envision a time in the near future when
the gentotyping of patients with respect to a panel
of cytokines, chemokines, and adhesion molecules
will complement traditional histocompatibility typ-
ing and increase our ability to predict the risk of
transplant-related toxicity. Such an expanded eval-
uation will make hematopoietic stem-cell transplan-
tation safer and improve the availability of this in-
tensive therapy for patients who need it.
From the Blood and Marrow Transplant Program, University of
Michigan Comprehensive Cancer Center (K.R.C., J.L.M.F.); and the
Departments of Internal Medicine (J.L.M.F.) and Pediatrics (K.R.C.,
J.L.M.F.), University of Michigan Medical School both in Ann
Arbor.
man growth), deceleration of growth immediately
after birth, a prolonged growth phase during child-
hood, prepubertal deceleration, and a pronounced
adolescent growth spurt. Although some of these
n engl j med 349;23 www.nejm.org december 4, 2003
 PERSPECTIVE
aspects are shared with other mammalian species,
others are characteristic only of Homo sapiens and are
not replicated even in other primates.
The intricacy of the human growth curve (see
Figure) is the product of an evolutionary process
expressing the sum effect of multiple genes whose
interplay determines a pattern of growth that reflects
the survival needs of our species. Given the complex-
ity of vertebrate and, especially, human growth, it is
reasonable to assume that a large number of genet-
ic factors are involved in the control of stature, a hy-
pothesis supported by the existence of multiple clin-
ical disorders characterized by growth failure. It is
therefore all the more surprising that a series of ele-
gant investigations in mice, complemented by case
Birth
CrownHeel Length Velocity (cm/4 wk)
10
8
6
4 tenuation in utero but profound postnatal growth
2 No GH
No IGF
0
10 20 30 40
Postmenstrual Direct sex
Age (wk) steroid effect
50th percentile
normal GH
No GH or no IGF-I
0 2 4 6 8 10 12 14 16
Age (yr)
Figure. Roles of Insulin-like Growth Factor (IGF) and Growth Hormone (GH)
in Prenatal and Postnatal Growth.
The upper (gray) line of the height-velocity curve in both panels approximates
the 50th percentile in boys. Different scales are used for prenatal growth (ex-
pressed as crownheel length velocity in centimeters per four weeks) and
postnatal height velocity (expressed as centimeters per year). The lower (red)
line in the postnatal height-velocity curves indicates the expected growth rate
in children totally lacking GH. Clinical evidence suggests that a similar line
can be drawn for children with severe IGF deficiency. The shaded region thus
reflects IGF-dependent growth. A small, direct sex steroid effect that is inde-
pendent of IGF is seen during puberty. Prenatally, the red line reflects the best
estimate of intrauterine growth in the absence of IGFs (derived from limited
case reports and murine models). IGF-dependent growth in prenatal life is
largely independent of GH, except for a small effect in the last few weeks be-
fore birth. (Modified from Daughaday WH and Rotwein P. Endocr Rev 1989;
10:68-91.)
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Insulin-like Growth Factors and the Basis of Growth
studies in humans, have convincingly demonstrat-
ed the critical role of the insulin-like growth factor
(IGF) system in all phases of mammalian growth,
including intrauterine, childhood, and pubertal.
The existence of IGFs was first proposed in 1957
on the basis of studies indicating that growth hor-
mone did not directly stimulate the incorporation
of sulfate into cartilage but rather acted through
a serum factor. This factor was originally termed
sulfation factor, then somatomedin, and ulti-
mately, insulin-like growth factor I (IGF-I) and II
(IGF-II). Subsequent investigations demonstrat-
ed that growth hormone (GH), after binding to its
transmembrane receptor, initiated a complex sig-
naling cascade leading to transcriptional regulation
of the gene for IGF-I and related genes. Thus, the
growth characteristics of patients with severe IGF
deficiency, resulting from homozygous mutations
in the gene for the GH receptor (or the GH signal-
ing protein signal transducer and activator of tran-
scription 5b [Stat5b]), were indistinguishable from
those of children with congenital GH deficiency.
Such patients typically had only minimal growth at-
failure, thereby underscoring the critical role of the
GH-IGF system in postnatal growth. The contribu-
20 tion of the GH-IGF axis to prenatal growth, however,
18 was less clear, since congenital defects of the se-
Height Velocity (cm/yr)
16 cretion or action of GH had limited effects on in-
14
trauterine growth and experimental ablation of the
12
pituitary only minimally impaired prenatal growth
10
8
in animals.
6 The concept that GH-independent IGF produc-
4 tion had a role in fetal growth emerged from stud-
2 ies of mouse mutants with defective genes for IGFs
0 or their receptors. Targeted disruption of the mouse
18
gene for IGF-II resulted in a 40 percent reduction
in fetal growth but otherwise normal postnatal
growth. Disruption of the gene for IGF-I led to a
similar decrease in birth weight but was also char-
acterized by persistent postnatal growth failure, so
that mice with the gene disrupted grew to only 30
percent of normal size as adults. Most striking, how-
ever, were the phenotypic consequences of dele-
tion of the gene for the IGF-I receptor (IGF-IR), a
transmembrane tyrosine kinase that mediates the
growth-promoting actions of both IGFs. Mice with
this deletion had birth weights that were only 45
percent of normal and generally died within hours
after birth from respiratory insufficiency resulting
from muscular hypoplasia.
The relevance of these findings in mice for hu-
man growth was supported by the report of a pa-
2185
PERSPECTIVE
tient with combined prenatal and postnatal growth
failure who was found to be homozygous for a de-
letion in the IGF-I gene. The clinical implications of
molecular defects of the IGF-I receptor were less
certain, however. Patients with deletions of chromo-
some 15q and consequent haploinsufficiency for the
IGF-IR gene generally have growth retardation, but
the potential contribution of the loss of contiguous
genes has been unclear. Similarly, studies suggest-
ing that IGF resistance has a role in the growth fail-
ure of the African Efe Pygmy have been inconclu-
sive, since no underlying molecular defect has been
identified.
A report by Abuzzahab et al. in this issue of the
Journal (pages 22112222) provides the most con-
vincing evidence to date that molecular abnormali-
ties of the IGF-I receptor can, as in the mouse mod-
el, result in combined intrauterine and postnatal
growth failure. One of 42 children with intrauter-
ine growth retardation and subsequent short stat-
ure was found to be a compound heterozygote for
point mutations in the IGF-IR gene; in a second study
of children with short stature despite elevated se-
rum IGF-I concentrations, one child with a history
of intrauterine growth retardation was identified
with heterozygosity for a nonsense mutation of the
IGF-IR gene.
The combination of data from targeted gene
Incentive-Based Formularies
Cindy Parks Thomas, Ph.D.
While much of the nation has been following the
deliberations in Congress over a Medicare drug ben-
efit, a quiet revolution has been taking place in the
way benefits are managed for the 200 million Amer-
icans who already have insurance for prescription
drugs. Just 10 years ago, most insured persons were
required to make a standard copayment of $5 or
less for a prescription, regardless of the type of med-
ication they purchased. Now, incentive-based for-
mularies are standard, with the amount of copay-
ments depending on the type of drug prescribed;
the contracts among the insurer, the manufacturer,
and the pharmacy; and the price differential be-
tween the selected drug and reasonable low-cost
2186
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Insulin-like Growth Factors and the Basis of Growth
disruptions in the mouse and case studies in hu-
mans has thus established the unequivocal role of
the IGF system as the main driver of embryonic, fe-
tal, and postnatal growth. The prenatal contribution
of the IGFs is largely independent of GH, presum-
ably representing the combined influences of pla-
cental sufficiency, fetal nutrition, and insulin, each
of which has been shown to affect fetal IGF concen-
trations, and a variety of as yet unidentified factors.
Shortly before birth, GH-dependent IGF-I produc-
tion emerges as the critical regulator of skeletal
growth, with minor direct contributions from sex
steroids at the time of puberty.
Although molecular defects of the IGF system
currently appear to be rare causes of intrauterine or
postnatal growth failure, the case reports described
by Abuzzahab et al. provide incontrovertible evi-
dence that the IGFs have a key role in mammalian
growth. It is likely that they will be followed by re-
ports of milder phenotypes associated with partial
defects. Even though the original somatomedin hy-
pothesis has required modification over the 46 years
since it was published, its fundamental conclusion
about the critical role of the IGFs in growth re-
mains sound.
From the Lucile Packard Foundation for Childrens Health, Stan-
ford University, Palo Alto, Calif.; and the Department of Pediatrics,
Oregon Health and Science University, Portland.
substitutes. For specific drugs, an insured person
may be asked to pay up to half of the full price; un-
der some insurance plans, members commonly
contribute one third of their overall prescription
costs. How this transformation in cost sharing af-
fects patients, their health care providers, and phar-
maceutical expenditures has been the subject of sev-
eral studies. The article by Huskamp and colleagues
in this issue of the Journal (pages 22242232) is
the most recent contribution.
The goal of incentive-based formularies is to
encourage people to choose lower-cost prescrip-
tion drugs, thereby creating cost savings for the
health plan, which can, in theory, then be passed on
n engl j med 349;23 www.nejm.org december 4, 2003